Kelsoe JR.
Arguments for the genetic basis of the bipolar spectrum.
J Affect Disord. 2003 Jan;73(1-2):183-97.
"Family members of bipolar probands have been repeatedly shown to have an increased risk for mood disorders. However, a range of different syndromes in the bipolar spectrum are commonly observed in these relatives. This suggests the hypothesis that these different syndromes may be genetically related. It further suggests that bipolar disorder may be better conceptualized from a genetic standpoint as a quantitative trait. In such a model, the same genes may predispose to a variety of phenotypes ranging from schizoaffective disorder to cyclothymic temperament. Previous attempts to test such a multifactorial model have provided some limited support. However, other studies argue that some forms of bipolar disorder such as bipolar II may be genetically distinct. In this review, various quantitative and categorical models of illness are considered and the data supporting them reviewed. It is proposed that the existing data may best fit a model in which different sets of genes predispose to overlapping phenotypes that are in part both quantitative and distinct in nature." [Abstract]

Becker KG.
The common variants/multiple disease hypothesis of common complex genetic disorders.
Med Hypotheses. 2004;62(2):309-17.
"Unlike simple rare Mendelian disorders, the genetic basis for common disorders is unclear. A general model of the genetics of common complex disorders is proposed which emphasizes the shared nature of common alleles in related common disorders, such as schizophrenia and bipolar disorder, Type II diabetes and obesity, and among autoimmune diseases. This model, the common variants/multiple disease hypothesis, emphasizes that many disease genes may not be disease specific. Common deleterious alleles, found at a relatively high frequency in the population may play a role in related clinical phenotypes in the context of different genetic backgrounds and under different environmental conditions." [Abstract]

Barrett TB, Hauger RL, Kennedy JL, Sadovnick AD, Remick RA, Keck PE, McElroy SL, Alexander M, Shaw SH, Kelsoe JR.
Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder.
Mol Psychiatry. 2003 May;8(5):546-57.
"In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5'-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2)=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD." [Abstract]

On Site Link: Bipolar Disorder and GRK3

ALEXANDER B. NICULESCU, III, DAVID S. SEGAL, RONALD KUCZENSKI, THOMAS BARRETT, RICHARD L. HAUGER, and JOHN R. KELSOE
Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach
Physiol. Genomics 4: 83-91, 2000.
"We have used methamphetamine treatment of rats as an animal model for psychotic mania. Specific brain regions were analyzed comprehensively for changes in gene expression using oligonucleotide GeneChip microarrays. The data was cross-matched against human genomic loci associated with either bipolar disorder or schizophrenia. Using this convergent approach, we have identified several novel candidate genes (e.g., signal transduction molecules, transcription factors, metabolic enzymes) that may be involved in the pathogenesis of mood disorders and psychosis. Furthermore, for one of these genes, G protein-coupled receptor kinase 3 (GRK3), we found by Western blot analysis evidence for decreased protein levels in a subset of patient lymphoblastoid cell lines that correlated with disease severity. Finally, the classification of these candidate genes into two prototypical categories, psychogenes and psychosis-suppressor genes, is described.
...
G protein-coupled receptor kinase 3. G protein-coupled receptor kinase 3 (GRK3) mediates homologous desensitization for a variety of neurotransmitters by phosphorylation of G protein-coupled receptors (GPCRs). GRK3 maps to human chromosome 22q11. This region had been previously implicated in bipolar disorder by our group (32, 38) and others (11, 15). In fact, 22q yielded the highest LOD scores of any chromosomal region in our genome survey (results to be reported separately). Consistent with many findings in this field, this linkage peak was broad and spanned nearly 20 cM. One of the highest LOD scores in this region was 2.2 at D22S419, which maps to within 40 kb of GRK3. This marker is also quite close to the markers identified in the two other independent positive linkage reports for 22q in bipolar disorder. A marker within the GRK3 gene, D22S315, has also been implicated in a study of eye tracking and evoked potential abnormalities in schizophrenia (44).
The known physiological role of GRK3, described in more detail below, suggests the hypothesis that a defect in its function could lead to supersensitivity to dopamine or a defect in the homeostatic adaptation to dopamine, which in turn could predispose to illness." [Full Text]

Potash JB, Zandi PP, Willour VL, Lan TH, Huo Y, Avramopoulos D, Shugart YY, MacKinnon DF, Simpson SG, McMahon FJ, DePaulo JR Jr, McInnis MG.
Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder.
Am J Psychiatry 2003 Apr;160(4):680-6
"OBJECTIVE: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and/or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder/schizophrenia linkage overlap. METHOD: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder. RESULTS: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings. CONCLUSIONS: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region." [Abstract]

Stopkova P, Saito T, Fann CS, Papolos DF, Vevera J, Paclt I, Zukov I, Stryjer R, Strous RD, Lachman HM.
Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.
Am J Med Genet. 2003 Nov 15;123B(1):50-8.
"Lithium is a potent noncompetitive inhibitor of inositol monophosphatases, enzymes involved in phosphoinositide (PI) and inositol phosphate metabolism. A critical component of the PI pathway is phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)), which is hydrolyzed to second messengers and has a direct role in synaptic vesicle function. Interestingly, a number of genes involved in the synthesis and dephosphorylation of PtdIns(4,5)P(2) are found in regions of the genome previously mapped in bipolar disorder (BD) including 10p12, 21q22, and 22q11, among others. Some of these regions overlap with loci mapped in schizophrenia (SZ). One gene involved in PI metabolism that maps to a region of interest is 10p12-linked PIP5K2A, a member of the phosphatidylinositol 4-phosphate 5-kinase family. Polymorphism screening revealed the existence of an imperfect CT repeat polymorphism located near the exon 9-intron 9 splice donor site. A modest difference was found in the distribution of alleles from this highly polymorphic variant when bipolar and schizophrenic subjects were compared with controls; relatively rare short repeat variants were found more commonly in patients and homozygosity for a common long repeat variant was found more commonly in controls. These data suggest that the imperfect CT repeat in PIP5K2A intron 9 should be further investigated as a possible candidate allele for 10p12-linked psychiatric disorders." [Abstract]

On Site Link: Bipolar Disorder and PIP2

Maziade M, Roy MA, Rouillard E, Bissonnette L, Fournier JP, Roy A, Garneau Y, Montgrain N, Potvin A, Cliche D, Dion C, Wallot H, Fournier A, Nicole L, Lavallee JC, Merette C.
A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes.
Mol Psychiatry 2001 Nov;6(6):684-93
"We report the first stage of a genome scan of schizophrenia (SZ) and bipolar disorder (BP) covering 18 candidate chromosomal areas. In addition to testing susceptibility loci that are specific to each disorder, we tested the hypothesis that some susceptibility loci might be common to both disorders. A total of 480 individuals from 21 multigenerational pedigrees of Eastern Quebec were evaluated by means of a consensus best-estimate diagnosis made blind to diagnoses in relatives and were genotyped with 220 microsatellite markers. Two-point and multipoint model-based linkage analyses were performed and mod scores (Z, for max Z(max)) are reported. The strongest linkage signals were detected at D18S1145 (in 18q12; Z = 4.03) for BP, and at D6S334 (in 6p 22-24; Z(het) = 3.47; alpha = 0.66) for SZ. Three other chromosomal areas (3q, 10p, and 21q) yielded linkage signals. Chromosomes 3p, 4p, 5p, 5q, 6q, 8p, 9q, 11q, 11p, 12q, 13q, 18p and 22q showed no evidence of linkage. The 18q12 results met the Lander and Kruglyak (1995) criterion for a genome-wide significant linkage and suggested that this susceptibility region may be shared by SZ and BP. The 6p finding provided confirmatory evidence of linkage for SZ. Our results suggest that both specific and common susceptibility loci must be searched for SZ and BP." [Abstract]

Foroud T, Castelluccio PF, Koller DL, Edenberg HJ, Miller M, Bowman E, Rau NL, Smiley C, Rice JP, Goate A, Armstrong C, Bierut LJ, Reich T, Detera-Wadleigh SD, Goldin LR, Badner JA, Guroff JJ, Gershon ES, McMahon FJ, Simpson S, MacKinnon D, McInnis M, Stine OC, DePaulo JR, Blehar MC, Nurnberger JI Jr.
Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees.
Am J Med Genet 2000 Feb 7;96(1):18-23
"As part of a four-center NIMH Genetics Initiative on Bipolar Disorder, a genome screen using 365 markers was performed on 540 DNAs from 97 families, enriched for affected relative pairs. This is the largest uniformly ascertained and assessed linkage sample for this disease, and includes 232 subjects diagnosed with bipolar I (BPI), 32 with schizo-affective, bipolar type (SABP), 72 with bipolar II (BPII), and 88 with unipolar recurrent depression (UPR). A hierarchical set of definitions of affected status was examined. Under Model I, affected individuals were those with a diagnosis of BPI or SABP, Model II included as affected those fitting Model I plus BPII, and Model III included those fitting Model II plus UPR. This data set was previously analyzed using primarily affected sib pair methods. We report the results of nonparametric linkage analyses of the extended pedigree structure using the program Genehunter Plus. The strongest finding was a lod score of 2.5 obtained on chromosome 10 near the marker D10S1423 with diagnosis as defined under Model II. This region has been previously implicated in genome-wide studies of schizophrenia and bipolar disorder. Other chromosomal regions with lod scores over 1.50 for at least one Model Included chromosomes 8 (Model III), 16 (Model III), and 20 (Model I)." [Abstract]

Straub RE, Lehner T, Luo Y, Loth JE, Shao W, Sharpe L, Alexander JR, Das K, Simon R, Fieve RR, et al.
A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3.
Nat Genet 1994 Nov;8(3):291-6
"In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder." [Abstract]

Liu J, Juo SH, Terwilliger JD, Grunn A, Tong X, Brito M, Loth JE, Kanyas K, Lerer B, Endicott J, Penchaszadeh G, Gilliam TC, Baron M.
A follow-up linkage study supports evidence for a bipolar affective disorder locus on chromosome 21q22.
Am J Med Genet 2001 Mar 8;105(2):189-94
"Evidence for linkage between bipolar affective disorder (BP) and 21q22 was first reported by our group in a single large pedigree with a lod score of 3.41 with the PFKL locus. In a subsequent study, with denser marker coverage in 40 multiplex BP pedigrees, we reported supporting evidence with a two-point lod score of 2.76 at the D21S1260 locus, about 6 cM proximal to PFKL. For cost-efficiency, the individuals genotyped in that study comprised a subset of our large pedigree sample. To augment our previous analysis, we now report a follow-up study including a larger sample set with an additional 331 typed individuals from the original 40 families, improved marker coverage, and an additional 16 pedigrees. The analysis of all 56 pedigrees (a total of 862 genotyped individuals vs. the 372 genotyped previously), the largest multigenerational BP pedigree sample reportedly analyzed to date, supports our previous results, with a two-point lod score of 3.56 with D21S1260. The 16 new pedigrees analyzed separately gave a maximum two-point lod score of 1.89 at D21S266, less than 1 cM proximal to D21S1260. Our results are consistent with a putative BP locus on 21q22." [Abstract]

Kaneva RP, Chorbov VM, Milanova VK, Kostov CS, Nickolov KI, Chakarova CF, Stoyanova VS, Nikolova-Hill AN, Krastev SK, Onchev GN, Kremensky IM, Kalaydjieva LV, Jablensky AV.
Linkage analysis in bipolar pedigrees adds support for a susceptibility locus on 21q22.
Psychiatr Genet. 2004 Jun;14(2):101-106. [Abstract]

Nagamine K, Kudoh J, Minoshima S, Kawasaki K, Asakawa S, Ito F, Shimizu N.
Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain.
Genomics 1998 Nov 15;54(1):124-31
"We have isolated cDNA clones for a novel human protein, TRPC7 (transient receptor potential-related channels), which consists of 1503 amino acid residues from the fetal brain and caudate nucleus cDNA libraries. Northern blot analysis indicated that the TRPC7 gene is highly expressed as a 6.5-kb transcript in brain. The TRPC7 protein has significant homology with Caenorhabditis elegans hypothetical proteins T01H8.5, C05C12.3, and F54D1.5 and with Drosophila and human transient receptor potential (trp) proteins. The TRPC7 protein has seven putative transmembrane domains that probably constitute a Ca2+ channel as in the above-mentioned proteins. Genomic sequencing revealed that the TRPC7 gene consists of 32 exons spanning approximately 90 kb. The TRPC7 gene was mapped between D21S400 and D21S171 on human chromosome 21q22.3, 14 kb distal to a NotI site in D21S400. This novel TRPC7 gene could be a candidate gene for genetic disorders such as bipolar affective disorder, nonsyndromic hereditary deafness, Knobloch syndrome, and holoprosencephaly, which were mapped to this region." [Abstract]

Yoon IS, Li PP, Siu KP, Kennedy JL, Macciardi F, Cooke RG, Parikh SV, Warsh JJ.
Altered TRPC7 gene expression in bipolar-I disorder.
Biol Psychiatry 2001 Oct 15;50(8):620-6
"BACKGROUND: As altered storage-operated calcium (Ca(2+)) entry (SOCE) may affect Ca(2+) homeostasis in bipolar disorder (BD), we determined whether changes occur in the expression of TRPC7 and SERCA2s, proteins implicated or known to be involved in SOCE, in B lymphoblast cell lines (BLCLs) from BD-I patients and comparison subjects. METHODS: mRNA levels were determined in BLCL lysates from BD-I, BD-II, and major depressive disorder patients, and healthy subjects by comparative reverse transcriptase-polymerase chain reaction, and BLCL basal intracellular Ca(2+) concentration ([Ca(2+)]B) was determined by ratiometric spectrophotometry using Fura-2, in aliquots of the same cell lines, at 13-16 passages in culture. RESULTS: TRPC7 mRNA levels were significantly lower in BLCLs from BD-I patients with high BLCL [Ca(2+)]B compared with those showing normal [Ca(2+)]B (-33%, p =.017) and with BD-II patients (-48%, p =.003), major depressive disorder patients (-47%, p =.049) and healthy subjects (-33%, p =.038). [Ca(2+)]B also correlated inversely with TRPC7 mRNA levels in BLCLs from the BD-I group as a whole (r = -.35, p =.027). CONCLUSIONS: Reduced TRPC7 gene expression may be a trait associated with pathophysiological disturbances of Ca(2+) homeostasis in a subgroup of BD-I patients." [Abstract]

Amore M, Strippoli P, Laterza C, Tagariello P, Vitale L, Casadei R, Frabetti F, Canaider S, Lenzi L, D'Addabbo P, Carinci P, Torroni A, Ferrari G, Zannotti M.
Sequence analysis of ADARB1 gene in patients with familial bipolar disorder.
J Affect Disord. 2004 Jul;81(1):79-85.
"Background: The ADARB1 gene is located in 21q22.3 region, previously linked to familial bipolar disorder, and its product has a documented action in the editing of the pre-mRNA of glutamate receptor B subunit. Dysfunction of glutamatergic neurotransmission could play an important role in the patophysiology of bipolar disorder (BD). Glutamate excitatory neurotransmission regulation is a possible mechanism of the initial effect of anticonvulsants in regulating mood. Methods: To investigate the hypothesis of an involvement of ADARB1 gene in the BD, the ADARB1 cDNA has been cloned and sequenced in seven selected bipolar I disorder patients with evidence of familiarity of mood disorders. A detailed investigation of the gene nucleotide sequence in the open reading frame has been performed. Results: No alteration in the sequence of the ADARB1 gene cDNA was found in any patient, except a common neutral polymorphism in three out of seven patients. Conclusions: Mutations in ADARB1 gene are not commonly associated with bipolar I disorder, therefore other genes in the 21q22 region could be associated with bipolar illness in some families, likely in the context of a multifactorial transmission model." [Abstract]

Ewald H, Mors O, Flint T, Kruse TA.
Linkage analysis between manic depressive illness and the region on chromosome 12q involved in Darier's disease.
Psychiatr Genet 1994 Winter;4(4):195-200
"Co-segregation between Darier's disease and manic depressive illness has been reported. A gene causing Darier's disease has recently been mapped to chromosome 12q23-q24.1, and this region may thus be considered a candidate region potentially containing a gene involved in the aetiology of manic depressive illness. At least one possible candidate gene for manic depressive illness, pro-melanin-concentrating hormone, is located on chromosome 12q23-q24. The present study investigated linkage between manic depressive illness and this region on chromosome 12q, using three microsatellite polymorphisms as genetic markers which flank the gene causing Darier's disease. For all dominant models close linkage was excluded. For broader phenotypic models linkage was excluded in the interval between markers, even in one large family alone." [Abstract]

Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O'Neill J, Smyth C, Moloney E, Murphy P, McQuillin A, Petursson H, Gurling H.
Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23-q24, and suggests the presence of additional loci on 1p and 1q.
Psychiatr Genet. 2003 Jun;13(2):77-84.
"OBJECTIVE: To localize genes conferring susceptibility to bipolar affective disorder. METHODS: Seven families were selected on the basis of containing multiple cases of bipolar affective disorder present in three or more generations, an absence of schizophrenia and unilineal transmission. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10 cM intervals across the whole genome. All markers were subjected to initial two-point and three-point analyses using LOD score and model-free analysis. All regions producing a result significant at P<0.01 were then subjected to four-point LOD score analysis under the assumption of heterogeneity. RESULTSA four-point LOD score of 2.8 was obtained using a dominant model and including unipolar cases as affected in the region of D12S342. Four-point LOD scores of 2 were obtained around D1S243, D1S251 and D3S1265. The positive results around D1S243 were accounted for by a LOD score of 3.1 occurring in a single pedigree. CONCLUSIONS: Since there has been previous strong support for linkage to the region of 12q23-q24 around D12S342, it now seems very probable that it does indeed contain a gene influencing susceptibility to bipolar affective disorder. Some evidence for linkage in the region of 1q near to D1S251 has been reported in one previous study. It therefore seems that this region of 1q and the region of 1p close to D1S243 may also harbour susceptibility genes." [Abstract]

Ewald H, Degn B, Mors O, Kruse TA.
Significant linkage between bipolar affective disorder and chromosome 12q24.
Psychiatr Genet 1998 Autumn;8(3):131-40
"Chromosome 12q23-q24.1 has been implied by a few linkage and association studies as a candidate region for affective disorder. The present study investigated for linkage between bipolar affective disorder and 16 microsatellite markers covering chromosome 12q22-q24 in two Danish families. Assuming homogeneity and a dominant mode of inheritance, a significant two-point lod score of 3.37 was found at D12S1639, when only bipolar patients were considered as affected. The lod score was supported by neighbouring markers. The empirical P-value for this lod score was 0.00002. Non-parametric analyses using SimIBD supported this finding, with P-values of 0.00003 and 0.005 at D12S1639. An overlapping segment of chromosome 12q24 was shared among all except one of the bipolar patients, with apparently different haplotypes in each family." [Abstract]

Lyons-Warren A, Chang JJ, Balkissoon R, Kamiya A, Garant M, Nurnberger J, Scheftner W, Reich T, McMahon F, Kelsoe J, Gershon E, Coryell W, Byerley W, Berrettini W, Depaulo R, McInnis M, Sawa A
Evidence of association between bipolar disorder and Citron on chromosome 12q24.
Mol Psychiatry. 2005 Jun 28; [Abstract]

Glaser B, Kirov G, Bray NJ, Green E, O'donovan MC, Craddock N, Owen MJ
Identification of a potential Bipolar risk haplotype in the gene encoding the winged-helix transcription factor RFX4.
Mol Psychiatry. 2005 May 3;
The gene encoding the transcription factor RFX4 represents an excellent neurobiological and positional candidate gene for Bipolar disorder due to the potential involvement of RFX4 proteins in the regulation of circadian rhythms and the proximity of the locus to numerous linkage signals on chromosome 12q23. In this study we have sought to identify common variants within the gene, which might confer risk to the disease in our large UK Caucasian sample of Bipolar patients (676 DSMIV Bipolar I probands, 690 controls). RFX4 was screened for sequence variants and the LD block structure across the genomic region determined using 22 biallelic polymorphisms (minor allele frequency >/=0.1). Through analysis of 10 haplotype-tagging markers and using a two-stage approach (subset I: 347 cases, 374 controls; subset II: 329 cases, 316 controls), we identified a haplotype at rs10778502 and ss24735177, which showed nominally significant disease association in our full sample (haplotype-specific P=0.002, global P=0.017; subset I: haplotype-specific P=0.0002, global P=0.0008; subset II: haplotype-specific P=0.572, global P=0.109). Evidence for potential disease association with mutations across the RFX4 region came also from the analysis of the nearby microsatellite D12S2072 (empirical P=0.009 in our full sample). Investigation of RFX4 brain cDNA tagged by rs10778502 provided evidence for significant allelic differences in expression (P<0.001), where some of the variance was accounted for by the genotype at ss24735177. Our findings thus indicate the potential functional relevance of the associated haplotype and now require replication in independent samples.Molecular Psychiatry advance online publication, 3 May 2005; doi:10.1038/sj.mp.4001689. [Abstract]

Glaser B, Kirov G, Green E, Craddock N, Owen MJ
Linkage disequilibrium mapping of bipolar affective disorder at 12q23-q24 provides evidence for association at CUX2 and FLJ32356.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):38-45.
Chromosome 12q23-q24 has been implicated by several linkage studies as harboring a gene for bipolar affective disorder. We performed linkage disequilibrium (LD) mapping with 17 microsatellite markers across a 1.6 Mb-wide segment forming the central part of our narrowest linkage region. A significant signal (P = 0.0016) was identified for one microsatellite marker in our UK Caucasian case-control sample (347 cases, 374 controls). Genes, including regulatory elements, around this marker were screened for mutations and the LD structure of the region determined by genotyping 22 SNPs and insertion/deletion polymorphisms in 94 individuals. A set of 11 haplotype tagging (ht) SNPs was genotyped in our sample using a two-stage procedure. Two SNPs (rs3847953 and rs933399) and an insertion/deletion with putative functional relevance (which are in high LD with each other and with the microsatellite marker) showed significant or nearly significant association with bipolar disorder after Bonferroni-correction (reaching nominal P values from P = 0.002 to P = 0.005). In a sample of 110 UK Caucasian parent-offspring trios there was a trend for an over transmission in the same direction that failed to meet conventional levels of statistical significance. Our data provide evidence for association between bipolar mood disorder and markers on chromosome 12q23-q24 but need replication in independent samples. [Abstract]

Shink E, Harvey M, Tremblay M, Gagné B, Belleau P, Raymond C, Labbé M, Dubé MP, Lafrenière RG, Barden N
Analysis of microsatellite markers and single nucleotide polymorphisms in candidate genes for susceptibility to bipolar affective disorder in the chromosome 12Q24.31 region.
Am J Med Genet B Neuropsychiatr Genet. 2005 Mar 14;
Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers D12S86 and D12S378 on chromosome 12 was the most probable genomic region to contain a susceptibility gene for affective disorders. Here we present a more detailed genetic analysis of a 7.7 Mb genomic region located on 12q24.31. This region was saturated with 20 microsatellite markers to refine the candidate region and linkage analysis performed in 41 families from the Saguenay-Lac-St-Jean (SLSJ) region of Quebec. The results of two point parametric analysis using MFLINK supported the presence of a susceptibility locus on chromosome 12q24.31. Association studies with microsatellite markers using a case/control sample from the same population (n = 401) and analyzed with CLUMP revealed significant allelic associations between the bipolar phenotype and markers NBG6 (P = 0.008) and NBG12 (P < 10(-3)). According to these results, we investigated candidate genes in the NBG12 area. We analyzed 32 genes for the presence of polymorphisms in coding sequences and intron/exon junctions and genotyped 22 non-synonymous SNPs in the SLSJ case/control sample. Two uncommon polymorphisms (minor allele frequency </= 0.03) found in KIAA1595 and FLJ22471 genes, gave P-values below 0.05 with the T1 statistic. Moreover, using haplotype analysis, a nearly significant haplotypic association was observed at the HM74 gene. These results do not give strong support for a role in the susceptibility to bipolar disorder of any of these genes analyzed. However, the significance of rare polymorphisms should be explored by further analyses. [Abstract]

Shink E, Morissette J, Sherrington R, Barden N
A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12.
Mol Psychiatry. 2005 Jun;10(6):545-52.
Our previous results pointed to a putative gene for susceptibility to bipolar affective disorder located on the chromosomal region 12q23-q24 that segregated in the Saguenay-Lac-St-Jean population of Quebec. We report here results from a second genome-wide scan based on the analysis of 380 polymorphic microsatellite markers. For the purpose of this analysis, an additional 18 families were recruited from the Saguenay-Lac-St-Jean region and pooled to our previous sample to improve its statistical power, giving a total of 394 sampled individuals. This work confirms the presence of a susceptibility locus for affective disorder on chromosome 12q24 with parametric LOD score value of 3.35 at D12S378 when pedigrees were broken into nuclear families and analysed under a recessive segregation model. This result was supported by neighbouring markers and by a LOD score value of 5.05 at D12S378 under model-free analysis. Other regions of lower interest were indicated on chromosomes 2, 5, 7, 9, 10, 17 and 20. [Abstract]

Shink E, Morissette J, Sherrington R, Barden N
A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12.
Mol Psychiatry. 2004 10 19;
Our previous results pointed to a putative gene for susceptibility to bipolar affective disorder located on the chromosomal region 12q23-q24 that segregated in the Saguenay-Lac-St-Jean population of Quebec. We report here results from a second genome-wide scan based on the analysis of 380 polymorphic microsatellite markers. For the purpose of this analysis, an additional 18 families were recruited from the Saguenay-Lac-St-Jean region and pooled to our previous sample to improve its statistical power, giving a total of 394 sampled individuals. This work confirms the presence of a susceptibility locus for affective disorder on chromosome 12q24 with parametric LOD score value of 3.35 at D12S378 when pedigrees were broken into nuclear families and analysed under a recessive segregation model. This result was supported by neighbouring markers and by a LOD score value of 5.05 at D12S378 under model-free analysis. Other regions of lower interest were indicated on chromosomes 2, 5, 7, 9, 10, 17 and 20.Molecular Psychiatry advance online publication, 19 October 2004; doi:10.1038/sj.mp.4001601. [Abstract]

Jacobsen NJ, Franks EK, Elvidge G, Jones I, McCandless F, O'Donovan MC, Owen MJ, Craddock N.
Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder.
Mol Psychiatry 2001 Jan;6(1):92-7
"Bipolar affective disorder is a genetically complex psychiatric disorder with a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier's disease was mapped to chromosome 12q23-q24.1 and linkage studies by us and others have subsequently implicated this region as harbouring a susceptibility gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a potential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this hypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random clustering of missense mutations in ATP2A2 in neuropsychiatric Darier patients, and functional data demonstrating the role of SERCA2 in intracellular calcium regulation. In a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23-q24.1 region, we performed mutational screening of the ATP2A2 coding sequence, promoter regions, and 3' untranslated region and identified six sequence variations. These were analysed in a large sample of bipolar patients (n = 324) and control subjects (n = 327). Analysis of allele and genotype distributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipolar disorder." [Abstract]

Verma R, Mukerji M, Grover D, B-Rao C, Das SK, Kubendran S, Jain S, Brahmachari SK
MLC1 gene is associated with schizophrenia and bipolar disorder in Southern India.
Biol Psychiatry. 2005 Jul 1;58(1):16-22.
BACKGROUND: Chromosome 22q13 has shown linkage with schizophrenia (SCZ) and bipolar affective disorder (BPAD). A missense mutation in MLC1 (putative cation-channel gene on 22q13) co-segregating with periodic catatonic schizophrenia has been reported. We have investigated the relationship of MLC1 with SCZ and BPAD in Southern India. METHODS: All exons and flanking intronic sequences of MLC1 were screened for novel variations. Case-control (216 BPAD, 193 SCZ, 116 control subjects) and family-based analyses (113 BPAD, 107 SCZ families) were performed to evaluate association of MLC1 with these disorders. RESULTS: We found 33 MLC1 sequence variations, including three novel mutations: Val210Ile, Leu308Gln, and Arg328His in six BPAD cases and Val210Ile in one control individual. Minor allele of a common variation, ss16339182 (in approximately 6 Kb Linkage-Disequilibrium [LD]-block) was associated with BPAD in case-control (p = .03) and family-based analyses (transmitted/nontransmitted [T/NT]-44/20; p = .003). Association was observed for rs2235349 and rs2076137 with SCZ and ss16339163 with BPAD in case-control study. Using Block 2 haplotype tagging single nucleotide polymorphisms (htSNPs), GC haplotype revealed association (p = .02) and excess transmission (p = .002) with BPAD. CONCLUSIONS: Association of MLC1 with SCZ and BPAD suggests involvement of a common pathway. Rare missense mutations and common variants associated with BPAD favors hypothesis about likely involvement of both rare and common polymorphisms in etiology of this complex disorder. [Abstract]

Liang SG, Sadovnick AD, Remick RA, Keck PE, McElroy SL, Kelsoe JR.
A linkage disequilibrium study of bipolar disorder and microsatellite markers on 22q13.
Psychiatr Genet 2002 Dec;12(4):231-5
"Bipolar disorder is a major psychiatric disorder characterized by extreme mood states that alternate between mania and depression. Family, twin, and adoption studies indicate a genetic component to the disease, but the etiology is suspected to be complex, with multiple genes contributing to an increased susceptibility to the disorder. We have previously reported a genome scan in which a genome-wide maximum LOD score indicated evidence of linkage at the marker D22S278 at 22q13. This area is of particular interest since it is also implicated in schizophrenia, and thus may harbor a susceptibility gene common to both disorders. In our further efforts to fine map this region, we examined 10 microsatellite markers spanning an interval of 2.3 MB in a set of 142 parent-proband triads. Linkage disequilibrium to illness was tested using the Transmission Disequilibrium Test. Haplotypes were determined and marker-to-marker linkage disequilibrium across the region was examined. D22S281 and D22S685 yielded suggestive evidence of linkage disequilibrium to bipolar disorder (empirical values of 0.023 and 0.036, respectively), but a marker-to-marker analysis indicates that a higher density screen is needed to adequately analyze this region." [Abstract]

John R. Kelsoe, M. Anne Spence, Erika Loetscher, Montserrat Foguet, A. Dessa Sadovnick, Ronald A. Remick, Pamela Flodman, Jason Khristich, Zofi Mroczkowski-Parker, John L. Brown, Diane Masser, Sharon Ungerleider, Mark H. Rapaport, William L. Wishart, and Hermann Luebbert
A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22
PNAS 98: 585-590; published online before print as 10.1073/pnas.011358498
"We examined 443 microsatellite markers in a set of 20 North American families with bipolar disorder. The genome-wide maximum was a lod score of 3.8 at D22S278 on 22q13 under the narrow diagnostic definition and an autosomal dominant model. Other regions with suggestive evidence for linkage include 3p21, 3q27, 5p15, 10q, 13q31-q34, and 21q22." [Full Text]

Greenwood TA, Alexander M, Keck PE, McElroy S, Sadovnick AD, Remick RA, Kelsoe JR.
Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder.
Am J Med Genet 2001 Mar 8;105(2):145-51
"A role for the dopamine transporter (DAT) in bipolar disorder is implicated by several lines of pharmacological evidence, as well as suggestive evidence of linkage at this locus, which we have reported previously. In an attempt to identify functional mutations within DAT contributing a susceptibility to bipolar disorder, we have screened the entire coding region, as well as significant portions of the adjacent non-coding sequence. Though we have not found a definitive functional mutation, we have identified a number of single nucleotide polymorphisms (SNPs) that span the gene from the distal promoter through exon 15. Of the 39 SNPs that are suitable for linkage disequilibrium (LD) studies, 14 have been analyzed by allele-specific PCR in a sample of 50 parent-proband triads with bipolar disorder. A haplotyped marker comprised of five SNPs, spanning the region between exon 9 and exon 15, was constructed for each individual, and transmission/disequilibrium test (TDT) analysis revealed this haplotype to be in linkage disequilibrium with bipolar disorder (allele-wise TDT p = 0.001, genotype-wise TDT p = 0.0004). These data replicate our previous finding of linkage to markers within and near DAT in a largely different family set, and provide further evidence for a role of DAT in bipolar disorder." [Abstract]

Keikhaee MR, Fadai F, Sargolzaee MR, Javanbakht A, Najmabadi H, Ohadi M
Association analysis of the dopamine transporter (DAT1)-67A/T polymorphism in bipolar disorder.
Am J Med Genet B Neuropsychiatr Genet. 2005 Mar 14;
An imbalance in the dopaminergic system in humans has been hypothesized to contribute to the pathogenesis of a number of psychiatric illnesses, including bipolar disorder, schizophrenia, and attention deficit hyperactivity disorder. We performed a case/control study on the DAT1 (HUGO approved symbol SL6A3) gene core promoter polymorphism -67A/T to analyze the possible association of either allele of this polymorphism with bipolar disorder. The allele and genotype frequencies of the polymorphism were studied in 136 patients and 163 controls, which were matched on the basis of sex, age, and ethnicity. The genotype frequencies in the patients group were as follows: AA 30.9%; AT 55.1%; TT 14% versus the genotype frequencies in the control group: AA 49%; AT 41.8%; TT 9.2% [chi(2) = 10.3, df = 2, OR = 2.15 (95% CI 1.34-3.47, P </= 0.006]. The T-allele of the -67A/T polymorphism revealed a approximately 1.4-fold excess in the patients group comparing with the controls (P </= 0.003). For the first time, these findings provide tentative evidence of the contribution of the DAT1 gene core promoter polymorphism to the etiopathophysiology of bipolar disorder at least in the Iranian population that we have studied. Interestingly, no allelic or genotype association was observed in the female patients (P </= 0.6 and P </= 0.7, respectively). Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings. (c) 2005 Wiley-Liss, Inc. [Abstract]

Kelsoe JR, Sadovnick AD, Kristbjarnarson H, Bergesch P, Mroczkowski-Parker Z, Drennan M, Rapaport MH, Flodman P, Spence MA, Remick RA.
Possible locus for bipolar disorder near the dopamine transporter on chromosome 5.
Am J Med Genet 1996 Nov 22;67(6):533-40
"The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission by mediating the active reuptake of synaptic dopamine. It is an important candidate gene for bipolar disorder because of data implicating dopamine abnormalities in mania, and because it is the site of action of amphetamine, which has activating and psychotogenic properties. DAT has recently been cloned by its homology to a family of transporters, and mapped to chromosome 5p15.3. We tested DAT for linkage to bipolar disorder in a collection of 21 families from the general North American population (University of California, San Diego/University of British Columbia [UCSD/UBC] families), three Icelandic pedigrees, and Old Order Amish pedigree 110. We examined three markers at DAT, including a 5' TaqI RFLP (HDAT-TaqI), a highly polymorphic variable number of tandem repeats marker (VNTR) (HDAT-VNTR1), and a 3' 40-bp repeat marker (HDAT-PCR1), as well as two nearby microsatellite markers, D5S392 and D5S406. A maximum lod score of 2.38 was obtained at D5S392 in one of the UCSD/UBC families under an autosomal-dominant model. A lod score of 1.09 was also obtained under the same dominant model in the Amish at HDAT-PCR1. In the combined set of families, a maximum lod score of 1.76 was obtained under an autosomal-recessive model at HDAT-TaqI. Positive results were also obtained at several markers, using three nonparametric methods in the UCSD/UBC family set: the affected pedigree member method (P = 0.001), an affected sib pair method (ESPA, P = 0.0008), and the transmission disequilibrium test (P = 0.024). These results suggest the presence of a susceptibility locus for bipolar disorder near the DAT locus on chromosome 5." [Abstract]

Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF, Brown A, Petryshen TL, Kirby AN, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Azevedo MH, Kennedy JL, Daly MJ, Sklar P, Pato CN.
Genomewide Linkage Analysis of Bipolar Disorder by Use of a High-Density Single-Nucleotide-Polymorphism (SNP) Genotyping Assay: A Comparison with Microsatellite Marker Assays and Finding of Significant Linkage to Chromosome 6q22.
Am J Hum Genet. 2004 Apr 1;74(5). [Epub ahead of print]
"We performed a linkage analysis on 25 extended multiplex Portuguese families segregating for bipolar disorder, by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the GeneChip Human Mapping 10K Array (HMA10K). Of these families, 12 were used for a direct comparison of the HMA10K with the traditional 10-cM microsatellite marker set and the more dense 4-cM marker set. This comparative analysis indicated the presence of significant linkage peaks in the SNP assay in chromosomal regions characterized by poor coverage and low information content on the microsatellite assays. The HMA10K provided consistently high information and enhanced coverage throughout these regions. Across the entire genome, the HMA10K had an average information content of 0.842 with 0.21-Mb intermarker spacing. In the 12-family set, the HMA10K-based analysis detected two chromosomal regions with genomewide significant linkage on chromosomes 6q22 and 11p11; both regions had failed to meet this strict threshold with the microsatellite assays. The full 25-family collection further strengthened the findings on chromosome 6q22, achieving genomewide significance with a maximum nonparametric linkage (NPL) score of 4.20 and a maximum LOD score of 3.56 at position 125.8 Mb. In addition to this highly significant finding, several other regions of suggestive linkage have also been identified in the 25-family data set, including two regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), as well as regions on chromosomes 4 (91 Mb, NPL = 2.97), 16 (20 Mb, NPL = 2.89), and 20 (60 Mb, NPL = 2.99). We conclude that at least some of the linkage peaks we have identified may have been largely undetected in previous whole-genome scans for bipolar disorder because of insufficient coverage or information content, particularly on chromosomes 6q22 and 11p11." [Abstract]

Cichon, Sven, Schumacher, Johannes, Muller, Daniel J., Hurter, Martina, Windemuth, Christine, Strauch, Konstantin, Hemmer, Susanne, Schulze, Thomas G., Schmidt-Wolf, Gabriele, Albus, Margot, Borrmann-Hassenbach, Margitta, Franzek, Ernst, Lanczik, Mario, Fritze, Jurgen, Kreiner, Roland, Reuner, Ulrike, Weigelt, Bettina, Minges, Jurgen, Lichtermann, Dirk, Lerer, Bernhard, Kanyas, Kyra, Baur, Max P., Wienker, Thomas F., Maier, Wolfgang, Rietschel, Marcella, Propping, Peter, Nothen, Markus M.
A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q
Hum. Mol. Genet. 2001 10: 2933-2944
"Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23." [Abstract]

Ewald H, Kruse TA, Mors O.
Genome wide scan using homozygosity mapping and linkage analyses of a single pedigree with affective disorder suggests oligogenic inheritance.
Am J Med Genet. 2003 Jul 1;120B(1):63-71.
"The present study reports results from a genome scan on a family with bipolar affective disorder in which the parents are first cousins and four of the offsprings and one grandchild have affective disorder. The study searched for risk loci for affective disorder by searching for homozygous segments or more complex inherited loci using parametric and non-parametric multipoint linkage analysis. In addition dominant, multipoint, affecteds-only linkage analyses were performed as a supplement to previous analyses. On chromosomes 2q31.3, 10, 12q24, and 21q22.3 evidence for a risk locus was obtained by parametric and/or non-parametric linkage analyses and by haplotype sharing. As other studies have found significant or suggestive linkage to bipolar disorder in these chromosome regions this suggests that an oligogenic mode of inheritance is possible in this family involving at least some of the loci. Finally, the work discusses whether homozygosity mapping using parametric and non-parametric linkage analyses may be of value for complex diseases including rare subphenotypes of such disorders." [Abstract]

Lundorf MD, Buttenschøn HN, Foldager L, Blackwood DH, Muir WJ, Murray V, Pelosi AJ, Kruse TA, Ewald H, Mors O
Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia.
Am J Med Genet B Neuropsychiatr Genet. 2005 May 5;135(1):94-101.
Recent evidence from postmortem studies suggests that GAD1 encoding the gamma-aminobutyric acid (GABA) synthetic enzyme GAD67 is a functional candidate susceptibility gene for both bipolar affective disorder (BPAD) and schizophrenia. Previous studies suggest linkage between D2S326 near GAD1 and BPAD. We systematically screened GAD1 exons, flanking intronic sequences, and the promoter sequence for polymorphisms in 16 BPAD patients and five controls from Denmark. We identified eight single nucleotide polymorphisms (SNPs) including two in the promoter sequence. An association study of SNPs covering GAD1 was performed in a Danish sample of 82 BPAD subjects and 120 controls and in a Scottish sample of 197 individuals with schizophrenia, 200 BPAD subjects and 199 controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated from genotype data from eight SNPs. Strong pairwise LD was observed among all pairs of neighboring markers. In the Danish sample, we found weak association between BPAD and two promoter SNPs spaced 1 kb apart. Furthermore, one, two, and three loci haplotype analysis showed weak association with BPAD in the Danish sample. The results from the association studies indicate that promoter variants are of importance for the Danish BPAD cases and we cannot reject the hypothesis of GAD1 as a functional candidate gene for BPAD. No association was observed between BPAD or schizophrenia and any of the investigated SNPs in the Scottish sample set. Thus the results obtained from the Scottish sample suggest that the GAD1 gene variants do not play a major role in the predisposition to schizophrenia. [Abstract]

McInnis MG, Lan TH, Willour VL, McMahon FJ, Simpson SG, Addington AM, MacKinnon DF, Potash JB, Mahoney AT, Chellis J, Huo Y, Swift-Scanlan T, Chen H, Koskela R, Colin Stine O, Jamison KR, Holmans P, Folstein SE, Ranade K, Friddle C, Botstein D, Marr T, Beaty TH, Zandi P, Raymond DePaulo J.
Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12.
Mol Psychiatry 2003 Mar;8(3):288-98
"The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41." [Abstract]

Macgregor S, Visscher PM, Knott SA, Thomson P, Porteous DJ, Millar JK, Devon RS, Blackwood D, Muir WJ
A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42.
Mol Psychiatry. 2004 Dec;9(12):1083-90.
In this study, we report a genome scan for psychiatric disease susceptibility loci in 13 Scottish families. We follow up one of the linkage peaks on chromosome 1q in a substantially larger sample of 22 families affected by schizophrenia (SCZ) or bipolar affective disorder (BPAD). To minimise the effect of genetic heterogeneity, we collected mainly large extended families (average family size >18). The families collected were Scottish, carried no chromosomal abnormalities and were unrelated to the large family previously reported as segregating a balanced (1:11) translocation with major psychiatric disease. In the genome scan, we found linkage peaks with logarithm of odds (LOD) scores >1.5 on chromosomes 1q (BPAD), 3p (SCZ), 8p (SCZ), 8q (BPAD), 9q (BPAD) and 19q (SCZ). In the follow-up sample, we obtained most evidence for linkage to 1q42 in bipolar families, with a maximum (parametric) LOD of 2.63 at D1S103. Multipoint variance components linkage gave a maximum LOD of 2.77 (overall maximum LOD 2.47 after correction for multiple tests), 12 cM from the previously identified SCZ susceptibility locus DISC1. Interestingly, there was negligible evidence for linkage to 1q42 in the SCZ families. These results, together with results from a number of other recent studies, stress the importance of the 1q42 region in susceptibility to both BPAD and SCZ. [Abstract]

Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK
Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder.
Am J Hum Genet. 2004 Nov;75(5):862-72.
Schizophrenia, schizoaffective disorder, and bipolar disorder are common psychiatric disorders with high heritabilities and variable phenotypes. The Disrupted in Schizophrenia 1 (DISC1) gene, on chromosome 1q42, was originally discovered and linked to schizophrenia in a Scottish kindred carrying a balanced translocation that disrupts DISC1 and DISC2. More recently, DISC1 was linked to schizophrenia, broadly defined, in the general Finnish population, through the undertransmission to affected women of a common haplotype from the region of intron 1/exon 2. We present data from a case-control study of a North American white population, confirming the underrepresentation of a common haplotype of the intron 1/exon 2 region in individuals with schizoaffective disorder. Multiple haplotypes contained within four haplotype blocks extending between exon 1 and exon 9 are associated with schizophrenia, schizoaffective disorder, and bipolar disorder. We also find overrepresentation of the exon 9 missense allele Phe607 in schizoaffective disorder. These data support the idea that these apparently distinct disorders have at least a partially convergent etiology and that variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders. [Abstract]

Thomson PA, Wray NR, Millar JK, Evans KL, Hellard SL, Condie A, Muir WJ, Blackwood DH, Porteous DJ
Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population.
Mol Psychiatry. 2005 Jul;10(7):657-68.
The Translin-associated factor X/Disrupted in Schizophrenia 1 (TRAX/DISC) region was first implicated as a susceptibility locus for schizophrenia by analysis of a large Scottish family in which a t(1;11) translocation cosegregates with schizophrenia, bipolar disorder and recurrent major depression. We now report evidence for association between bipolar disorder and schizophrenia and this locus in the general Scottish population. A systematic study of linkage disequilibrium in a representative sample of the Scottish population was undertaken across the 510 kb of TRAX and DISC1. SNPs representing each haplotype block were selected for case-control association studies of both schizophrenia and bipolar disorder. Significant association with bipolar disorder in women P=0.00026 (P=0.0016 in men and women combined) was detected in a region of DISC1. This same region also showed nominally significant association with schizophrenia in both men and women combined, P=0.0056. Two further regions, one in TRAX and the second in DISC1, showed weaker evidence for sex-specific associations of individual haplotypes with bipolar disorder in men and women respectively, P<0.01. Only the association between bipolar women and DISC1 remained significant after correction for multiple testing. This result provides further supporting evidence for DISC1 as a susceptibility factor for both bipolar disorder and schizophrenia, consistent with the diagnoses in the original Scottish translocation family.Molecular Psychiatry (2005) 10, 657-668. doi:10.1038/sj.mp.4001669 Published online 19 April 2005. [Abstract]

Ekholm JM, Kieseppa T, Hiekkalinna T, Partonen T, Paunio T, Perola M, Ekelund J, Lonnqvist J, Pekkarinen-Ijas P, Peltonen L.
Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder.
Hum Mol Genet. 2003 Aug 1;12(15):1907-15.
"We performed a genome-wide scan for susceptibility loci in bipolar disorder in a study sample colleted from the isolated Finnish population, consisting of 41 families with at least two affected siblings. We identified one distinct locus on 16p12 providing significant evidence for linkage in two-point analysis (Z(max)=3.4). Furthermore, three loci with a two-point LOD score >2.0 were observed with markers on 4q32, 12q23 and Xq25, the latter locus having been earlier identified in one extended Finnish pedigree. In the second stage we fine mapped these chromosomal regions and also genotyped additional family members. In the fine mapping stage, 4q32 provided significant evidence of linkage for the three-point analyses (Z(max)=3.6) and 16p12 produced a three-point LOD score of 2.7. Since the identified chromosomal regions replicate earlier linkage findings in either bipolar disorder or other mental disorders, they should be considered good targets for further genetic analyses." [Abstract]

Berrettini WH.
Molecular linkage studies of bipolar disorders.
Bipolar Disord 2001 Dec;3(6):276-83
"OBJECTIVES: To review the reports of linkage findings for bipolar disorder. METHODS: Literature review of published linkage findings in bipolar disorder. RESULTS: There are several regions of the human genome that have been implicated repeatedly by independent investigators. These include 4p16, 12q24, 18q22, 18p11, 21q21 and 22q11. Two of these regions (18p11 and 22q11) are also implicated in genome scans of schizophrenia, suggesting that these two distinct nosological categories may share some genetic susceptibility. This hypothesis can only be tested when the underlying genes are identified." [Abstract]

Stopkova P, Saito T, Papolos DF, Vevera J, Paclt I, Zukov I, Bersson YB, Margolis BA, Strous RD, Lachman HM.
Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia.
Biol Psychiatry. 2004 May 15;55(10):981-8.
"BACKGROUND: Genes involved in phosphoinositide (PI) lipid metabolism are excellent candidates to consider in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). One is PIK3C3, a member of the phosphatidylinositide 3-kinase family that maps closely to markers on 18q linked to both BD and SZ in a few studies. METHODS: The promoter region of PIK3C3 was analyzed for mutations by single-strand conformation polymorphism analysis and sequencing. A case-control association study was conducted to determine the distribution of variant alleles in unrelated patients from three cohorts. Electromobility gel shift assays (EMSA) were performed to assess the functional significance of variants. RESULTS: Two polymorphisms in complete linked disequilibrium with each other were identified, -432C- > T and a "C" insert at position -86. The -432T allele occurs within an octamer containing an ATTT motif resembling members of the POU family of transcription factors. In each population analyzed, an increase in -432T was found in patients. EMSAs showed that a -432T containing oligonucleotide binds to brain proteins that do not recognize -432C. CONCLUSIONS: A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients." [Abstract]

Goossens D, Van Gestel S, Claes S, De Rijk P, Souery D, Massat I, Van Den Bossche D, Backhovens H, Mendlewicz J, Van Broeckhoven C, Del-Favero J.
A novel CpG-associated brain-expressed candidate gene for chromosome 18q-linked bipolar disorder.
Mol Psychiatry 2003;8(1):83-9
"We previously identified 18q21-q22 as a candidate region for bipolar (BP) disorder and constructed a yeast artificial chromosome (YAC) contig map. Here we identified three potential CpG islands using CCG/CGG YAC fragmentation. Analysis of available genomic sequences using bioinformatic tools identified an exon of 3639 bp downstream of a CpG island of 1.2 kb containing a putative transcription initiation site. The exon contained an open reading frame coding for 1212 amino acids with significant homology to the SART-2 protein; weaker homology was found with a series of sulphotransferases. Alignment of cDNA sequences of corresponding ESTs and RT-PCR sequencing predicted a transcript of 9.5 kb which was confirmed by Northern blot analysis. The transcript was expressed in different brain areas as well as in multiple other peripheral tissues. We performed an extensive mutation analysis in 113 BP patients. A total of nine single nucleotide polymorphisms (SNPs) were identified. Five SNPs predicted an amino acid change, of which two were present in BP patients but not in 163 control individuals." [Abstract]

Schulze TG, Chen YS, Badner JA, McInnis MG, DePaulo JR, McMahon FJ.
Additional, physically ordered markers increase linkage signal for bipolar disorder on chromosome 18q22.
Biol Psychiatry 2003 Feb 1;53(3):239-43
"We recently reported evidence of linkage of bipolar disorder to chromosome 18q, with a paternal logarithm of odds (LOD) score of 4.67 (p =.004) in a clinically defined subset of families. Like other linkage studies, we had to rely on imprecise genetic maps to establish the marker order. Here, we test for linkage in the same sample with a denser set of markers, now physically ordered according to the draft sequence of the human genome.Families were ascertained through probands with bipolar I disorder and diagnosed with reliable methods. Genotypes were generated for 12 microsatellite markers within an 11-centimorgan (cM) region of chromosome 18q22. Multipoint affected sib-pair linkage analysis was performed in a set of 16 nuclear families.The additional markers significantly increased the total genetic information extracted from our sample. We also observed an increase in the LOD score (to 5.42, p =.0066) and linkage resolution. The approximate 1-LOD support interval is now 9 male cM.The results strengthen our previous findings and further define a region suitable for genetic fine-mapping analysis on chromosome 18q. Our data suggest that a dense set of markers, when physically ordered, can increase the informational value of genetic linkage signals." [Abstract]

Borglum AD, Kirov G, Craddock N, Mors O, Muir W, Murray V, McKee I, Collier DA, Ewald H, Owen MJ, Blackwood D, Kruse TA.
Possible parent-of-origin effect of Dopa decarboxylase in susceptibility to bipolar affective disorder.
Am J Med Genet 2003 Feb 15;117B(1):18-22
"Dopa decarboxylase (DDC) catalyses the synthesis of both dopamine and serotonin as well as trace amines suggested to possess neuromodulating capabilities. We have previously reported evidence suggesting an association between DDC and bipolar affective disorder (BPAD) [Borglum et al., 1999]. To further investigate the possible role of DDC in BPAD, we analyzed a 1- and a 4-bp deletion variant-both of putative functional significance-in two new samples: a case-control sample with 140 cases and 204 controls, and 100 case-parents trios. We also tested for association in subjects with familial disease in both the new and the previously investigated samples. The previously reported association was not replicated in either of the new samples. However, a preponderance of the 1-bp deletion was increased by analysis of the familial cases separately for all case-control samples investigated, indicating a possible association with familial disease (combined analysis, P = 0.02). In the trio sample, a preferential paternal transmission of the 4-bp deletion was observed (P = 0.006). DDC is located next to the imprinted gene GRB10, which is expressed specifically from the paternal allele in fetal brains. Increased transmission of paternal DDC alleles has also been suggested in attention deficit hyperactivity disorder. We suggest that DDC might confer susceptibility to BPAD predominantly when paternally transmitted." [Abstract]

OMIM - Online Mendelian Inheritance in Man: DOPA DECARBOXYLASE
[The dopa decarboxylase gene has been located at 7p11.]

Crowe RR, Vieland V.
Report of the Chromosome 5 Workshop of the Sixth World Congress on Psychiatric Genetics.
Am J Med Genet 1999 Jun 18;88(3):229-32
"In bipolar illness five genetically related pedigrees from the Saguenay-Lac-St. Jean region of Quebec identified a region of interest at 5q31.3-q35.1. This region overlaps with the D5S423 locus and includes the D5S812 locus and the 5q34 region, all of which are consistent with linkage in at least one other study." [Abstract]

Sklar P, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Verner A, Hudson TJ, Morley CP, Kennedy JL, Azevedo MH, Lander E, Daly MJ, Pato CN.
Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis.
Mol Psychiatry. 2003 Dec 30 [Epub ahead of print].
"Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island populations, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31-5q35 with strong linkage (NPL=3.09, P=0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL=3.10 for significant linkage. Additional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 additional families. The combined set of 40 families had a peak NPL=3.28 (P=0.00066) at markers D5S2112-D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia (peak NPL=3.03, P=0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases." [Abstract]

Severino G, Congiu D, Serreli C, De Lisa R, Chillotti C, Del Zompo M, Piccardi MP
A48G polymorphism in the D(1) receptor genes associated with bipolar I disorder.
Am J Med Genet B Neuropsychiatr Genet. 2005 Feb 9;134B(1):37-38.
Several lines of evidence point to a role for dopamine in mood disorders and, in particular, in bipolar disorders. In line with a considerable amount of evidence, the dopamine D(1) receptor gene (DRD1) is considered to be a good candidate gene for bipolar disorders. Several studies did not find any association between bipolar 1 patients and DRD1. In this study, we investigate a possible association between BP disorder and -48A/G polymorphism of the DRD1. We genotyped 107 bipolar 1 patients and 129 healthy control subjects of exclusively Sardinian descent. A statistically significant difference in genotype (chi(2) = 6.29, df = 2, P = 0.042) and allele (chi(2) = 5.46, df=1, P = 0.019; OR = 1.53, 95% CI = 1.08-2.16) frequencies was found, suggesting an association between the DRD1 gene and bipolar I disorder (BP I) in the Sardinian population. [Abstract]

Hong KS, McInnes LA, Service SK, Song T, Lucas J, Silva S, Fournier E, Leon P, Molina J, Reus VI, Sandkuijl LA, Freimer NB.
Genetic mapping using haplotype and model-free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31-33.
Am J Med Genet. 2004 Feb 15;125B(1):83-6.
"We report further evidence for our previous suggestion [Garner et al., 2001: Am J Hum Genet 68:1061-1064] of a locus on 5q predisposing to bipolar I disorder (BP-I) in an extended Costa Rican pedigree. We genotyped additional microsatellite markers in this region and applied a multi-point non-parametric linkage analysis (SimWalk2). Significant identity-by-descent allele sharing among affected relatives was observed for all of the 20 markers tested in a segment of approximately 15 cM. Most affected individuals shared a single haplotype over this region; breaks within this haplotype may suggest a more restricted candidate location for a BP-I gene. These results support the suggestion that a locus at 5q31-33, together with a previously reported locus at 18q22-23, may provide the major genetic risk for BP-I in this family." [Abstract]

Horiuchi Y, Nakayama J, Ishiguro H, Ohtsuki T, Detera-Wadleigh SD, Toyota T, Yamada K, Nankai M, Shibuya H, Yoshikawa T, Arinami T.
Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders.
Biol Psychiatry. 2004 Jan 1;55(1):40-5.
"BACKGROUND: The gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in the pathogenesis of mood disorders. The GABRA1 gene encodes one of the subunits of GABA-A receptor and is located on human chromosome 5q34-q35, which is a region reportedly linked to mood disorders. We examined the GABRA1 gene as a candidate for mood disorders. METHODS: We performed mutation screening of GABRA1 in 24 Japanese bipolar patients and evaluated associations in Japanese case-control subjects consisting of 125 patients with bipolar disorder, 147 patients with depressive disorders, and 191 healthy control subjects. Associations were confirmed in the National Institute of Mental Health (NIMH) Initiative Bipolar Pedigrees, which consists of 88 multiplex pedigrees with 480 informative persons. RESULTS: We identified 13 polymorphisms in the GABRA1 gene. Nonsynonymous mutations were not found. Association of a specific haplotype with affective disorders was suggested in the Japanese case-control population (corrected p=.0008). This haplotype association was confirmed in the NIMH pedigrees (p=.007). CONCLUSIONS: These results indicate that the GABRA1 gene may play a role in the etiology of bipolar disorders." [Abstract]

Serretti A, Macciardi F, Cusin C, Lattuada E, Lilli R, Di Bella D, Catalano M, Smeraldi E.
GABAA alpha-1 subunit gene not associated with depressive symptomatology in mood disorders.
Psychiatr Genet. 1998 Winter;8(4):251-4.
"Considerable evidence implicates the neurotransmitter gamma-aminobutyric acid (GABA) in the biochemical pathophysiology of mood disorders. In this study, we investigated the possibility that the gene for the gamma-aminobutyric acid type A (GABAA) receptor alpha-1 subunit (GABRA1) might be associated with depressive symptomatology in a sample of mood disorder subjects. Sixty-seven inpatients affected by unipolar (n = 37) and bipolar (n = 30) disorder (DSMIV) were assessed at admission by the Hamilton depression rating scale (HAMD) and were typed using polymerase chain reaction (PCR) techniques. GABRA1 variants were not associated with depressive symptomatology, and consideration of possible stratification effects such as sex, psychiatric diagnosis and illness severity did not reveal any association either. GABAA alpha-1 subunit gene is not, therefore, associated with depressive symptomatology in mood disorder subjects." [Abstract]

Serretti A, Macciardi F, Cusin C, Lattuada E, Lilli R, Di Bella D, Catalano M, Smeraldi E.
No interaction of GABA(A) alpha-1 subunit and dopamine receptor D4 exon 3 genes in symptomatology of major psychoses.
Am J Med Genet. 1999 Feb 5;88(1):44-9.
"Previously, we reported on an association of the dopamine receptor D4 (DRD4) gene with delusional symptomatology of major psychoses. However, despite the strength of the association, it only accounted for 2% of the variance, indicating that contributions from other genes were probable. In the present study, we investigated the original cohort of subjects to evaluate the gene for the gamma-aminobutyric acid type A (GABA(A)) receptor alpha-1 subunit (GABRA1). The possible association of GABRA1 with the psychopathology of major psychoses was tested both alone and in interaction with DRD4. Four hundred and sixty-one inpatients affected by major psychoses were assessed by the operational criteria checklist for psychotic illness (OPCRIT) and were also typed for the DRD4 and GABRA1 variants using PCR techniques. Mania, depression, delusion, and disorganization were the four symptomatologic factors used as phenotype definitions. GABRA1 variants were not associated with these symptomatologic factors, and consideration of possible stratification effects such as sex and psychiatric diagnosis also did not reveal any association. GABRA1 variants did not significantly influence the association of DRD4 with delusional symptoms. No interaction was observed on the other symptom factors. The GABA(A) alpha-1 subunit gene does not, therefore, interact with DRD4 in the symptomatology of major psychoses." [Abstract]

Otani K, Ujike H, Tanaka Y, Morita Y, Katsu T, Nomura A, Uchida N, Hamamura T, Fujiwara Y, Kuroda S
The GABA type A receptor alpha5 subunit gene is associated with bipolar I disorder.
Neurosci Lett. 2005 Jun 10-17;381(1-2):108-13.
Several genetic studies have revealed that bipolar disorders are linked with the chromosomal locus of 15q11-q13, where the gamma-aminobutyric acid (GABA) receptor alpha5 subunit gene (GABRA5) locates. GABA is one of the major neurotransmitters that may be involved in the pathogenesis of bipolar disorder. Five polymorphisms in the GABRA5 gene, -754C>T in the promoter region, IVS1-21G>A, IVS2-26T>A, (*)302C>T in 3'-UTR of exon 5, and a CA repeat polymorphism in the 3' flanking region were examined in a Japanese population. IVS1-21G>A exhibited significant differences in the distribution of the genotype and allele frequency in bipolar I disorder patients but not in bipolar II disorder patients, compared with control subjects. The haplotype analysis showed that IVS1-21G>A/IVS2-26A>T was associated with bipolar I disorder, and the IVS1-21A/IVS2-26T haplotype was a negative risk factor for susceptibility to the disorders (odds ratio: 0.57, 95% confidence interval: 0.44-0.73). These results suggest that the GABRA5 gene may confer susceptibility to bipolar I disorder. [Abstract]

Maziade M, Roy MA, Chagnon YC, Cliche D, Fournier JP, Montgrain N, Dion C, Lavallée JC, Garneau Y, Gingras N, Nicole L, Pirès A, Ponton AM, Potvin A, Wallot H, Mérette C
Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families.
Mol Psychiatry. 2005 May;10(5):486-99.
The goal of this study was to identify susceptibility loci shared by schizophrenia (SZ) and bipolar disorder (BP), or specific to each. To this end, we performed a dense genome scan in a first sample of 21 multigenerational families of Eastern Quebec affected by SZ, BP or both (N=480 family members). This probably constitutes the first genome scan of SZ and BP that used the same ascertainment, statistical and molecular methods for the concurrent study of the two disorders. We genotyped 607 microsatellite markers of which 350 were spaced by 10 cM and 257 others were follow-up markers in positive regions at the 10 cM scan. Lander and Kruglyak thresholds were conservatively adjusted for multiple testings. We maximized the lod scores (mod score) over eight combinations (2 phenotype severity levels x 2 models of transmission x 2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score >4.0: three for BP (15q11.1, 16p12.3, 18q12-q21) and two for the shared phenotype, that is, the common locus (CL) phenotype (15q26,18q12-q21). Nine mod scores exceeded the suggestive threshold of 2.6: three for BP (3q21, 10p13, 12q23), three for SZ (6p22, 13q13, 18q21) and three for the CL phenotype (2q12.3, 13q14, 16p13). Mod scores >1.9 might represent confirmatory linkages of formerly reported genomewide significant findings such as our finding in 6p22.3 for SZ. Several regions appeared to be shared by SZ and BP. One linkage signal (15q26) appeared novel, whereas others overlapped formerly reported susceptibility regions. Despite the methodological limitations we raised, our data support the following trends: (i) results from several genome scans of SZ and BP in different populations tend to converge in specific genomic regions and (ii) some of these susceptibility regions may be shared by SZ and BP, whereas others may be specific to each. The present results support the relevance of investigating concurrently SZ and BP within the same study and have implications for the modelling of genetic effects. [Abstract]

Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, Toyota T, Shimizu H, Yamada K, Yoshitsugu K, Hattori E, Yoshikawa T, Arinami T.
Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees.
Mol Psychiatry 2002;7(9):954-61
"Possible irregularities in serotonergic neurotransmission have been suggested as causes of a variety of neuropsychiatric diseases. We performed mutation and association analyses of the HTR4 gene, on 5q32, encoding the serotonin 4 receptor in mood disorders and schizophrenia. Mutation analysis was performed on the HTR4 exons and exon/intron boundaries in 48 Japanese patients with mood disorders and 48 patients with schizophrenia. Eight polymorphisms and four rare variants were identified. Of these, four polymorphisms at or in close proximity to exon d, g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164 (T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4), showed significant association with bipolar disorder with odds ratios of 1.5 to 2. These polymorphisms were in linkage disequilibrium, and only three common haplotypes were observed. One of the haplotypes showed significant association with bipolar disorder (P = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by transmission disequilibrium test in the NIMH Genetics Initiative Bipolar Pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (P = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (P = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT(4) receptor. These findings suggest that genomic variations in the HTR4 gene may confer susceptibility to mood disorder." [Abstract]

OMIM - Online Mendelian Inheritance in Man: 5-HT4 Receptor
[5-HT4 has been located at 5q31-q33]

Bonnier B, Gorwood P, Hamon M, Sarfati Y, Boni C, Hardy-Bayle MC.
Association of 5-HT(2A) receptor gene polymorphism with major affective disorders: the case of a subgroup of bipolar disorder with low suicide risk.
Biol Psychiatry 2002 May 1;51(9):762-5
"BACKGROUND: The implication of serotonin in suicide and affective disease explains why the 5-HT(2A) receptor gene has been proposed as a candidate gene in these disorders, although with conflicting results. METHODS: We analysed the distribution of the 5-HT(2A)-1438A/G genetic polymorphism in 192 patients with major affective disorder (127 bipolar disorders and 65 unipolar disorders) compared to 142 healthy control subjects. RESULTS: We found a higher frequency of the A allele in affected patients than in control subjects (p =.034), this difference being particularly striking for the subgroup of patients with type I bipolar disorder (p =.015). Patients with no personal and/or familial history of suicide attempts mainly accounted for the excess of the A allele in affected patients. CONCLUSIONS: The association detected in this study suggests that the 5-HT(2A) receptor gene may play a role in the genetic susceptibility to bipolar disorder, through a specific subgroup of bipolar type I patients with lower risk of suicidal behavior." [Abstract]

Chee IS, Lee SW, Kim JL, Wang SK, Shin YO, Shin SC, Lee YH, Hwang HM, Lim MR.
5-HT2A receptor gene promoter polymorphism -1438A/G and bipolar disorder.
Psychiatr Genet 2001 Sep;11(3):111-4
"Genetic factors, such as the genes involved in the serotonin pathway, probably play an important role in the pathogenesis of bipolar disorder, and serotonin type 2A (5-HT2A) receptor gene promoter polymorphism -1438A/G has been reported. This study investigated the association between -1438A/G polymorphism of 5-HT2A receptor gene promoter and bipolar disorder in a Korean population. Using the polymerase chain reaction, -1438A/G polymorphism typed in 142 patients with bipolar disorder and in 148 normal control subjects. Differences in genotype distributions and allele frequencies of -1438A/G between patients with bipolar disorder and normal control subjects were tested for significance using the chi-squared test. There were significant differences in genotype distributions [chi2 = 9.697, degrees of freedom (df) = 2, P = 0.008] and allele frequencies (chi2 = 7.284, df = 1, P = 0.007) of -1438A/G between patients with bipolar disorder and normal control subjects. Although further studies are necessary, these results in a Korean population suggest that -1438A/G polymorphism of 5-HT2A receptor gene promoter may be causally related to the development of bipolar disorder." [Abstract]

Ni X, Trakalo JM, Mundo E, Lee L, Parikh S, Kennedy JL.
Family-based association study of the serotonin-2A receptor gene (5-HT2A) and bipolar disorder.
Neuromolecular Med 2002;2(3):251-9
"OBJECTIVES: The serotonin 2A receptor gene (5-HT2A) is of great interest for research in neuropsychiatric disorders based on the observation that various neuroleptic agents and antidepressants bind with relatively high affinity at 5-HT2A receptors, and the fact that the receptor density in platelets tends to increase in depression. To test for the presence of association between 5-HT2A and bipolar disorder (BP), we studied a large number of triad families having probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or schizoaffective disorder, bipolar type. METHODS: Two polymorphisms of 5-HT2A, 102T/C, and His452Tyr were analyzed in the 274 bipolar triad families. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data. We also calculated the maternal transmission and paternal transmission for each allele and compared the mean ages of onset across probands grouped by genotype at each of the two markers. RESULTS: No significant transmission disequilibrium between the alleles of 5-HT2A and BP was found. Separate studies of the sub-phenotypes also failed to demonstrate significant association. However, we found a trend towards transmission disequilibrium with the haplotype 102C.His452 (p = 0.0504). This trend may become more significant with a larger sample size. SIGNIFICANCE: At present, results of this study suggest that the 5-HT2A is unlikely to play a major role in the genetic susceptibility to BP. Future studies will be directed towards increasing sample size, focusing on subtypes of BP or biochemical measures as phenotypes, and investigating other polymorphisms of 5-HT2A to provide more information at the DNA level." [Abstract]

Ranade SS, Mansour H, Wood J, Chowdari KV, Brar LK, Kupfer DJ, Nimgaonkar VL.
Linkage and association between serotonin 2A receptor gene polymorphisms and bipolar I disorder.
Am J Med Genet. 2003 Aug 15;121B(1):28-34.
"Several inconsistent associations between bipolar I disorder (BD1) and polymorphisms of the genes encoding the serotonin 2A receptor (HTR2A) have been published. We conducted the Transmission Disequilibrium Test (TDT) and case-control comparisons involving nine single nucleotide polymorphisms at the serotonin 2A receptor gene (four SNPs of HTR2A exons and five flanking SNPs). Comparison of BD1 cases (n = 93) with a group of unrelated population based controls (n = 92) revealed associations with SNPs on exons 2 and 3 (516C/T and 1354C/T, respectively), consistent with haplotype-based differences. Analysis of the cases and their available parents using the TDT suggested significant linkage and associations with 1354C/T, as well as haplotypes bearing this SNP. Our results support an etiological role for HTR2A in BD1. In view of the relatively small sample, replicate studies using large samples are needed." [Abstract]

OMIM - Online Mendelian Inheritance in Man: 5-HT2A Receptor
[5-HT2A has been located at 13q14-q21]

Etain B, Rousseva A, Roy I, Henry C, Malafosse A, Buresi C, Preisig M, Rayah F, Leboyer M, Bellivier F
Lack of association between 5HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample.
Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):29-33.
Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study. [Abstract]

Detera-Wadleigh SD, Badner JA, Yoshikawa T, Sanders AR, Goldin LR, Turner G, Rollins DY, Moses T, Guroff JJ, Kazuba D, Maxwell ME, Edenberg HJ, Foroud T, Lahiri D, Nurnberger JI Jr, Stine OC, McMahon F, Meyers DA, MacKinnon D, Simpson S, McInnis M, DePaulo JR, Rice J, Goate A, Gershon ES, et al.
Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q.
Am J Med Genet 1997 May 31;74(3):254-62
"An initial genome scan was performed on 540 individuals from 97 families segregating bipolar disorder, collected through the National Institutes of Mental Health Genetics Initiative. We report here affected-sib-pair (ASP) data on 126 marker loci (approximately 68,000 genotypes) mapping to chromosomes 4, 7, 9, 18, 19, 20, and 21q, under three affection status models. Modest increases in identical-by-descent (IBD) allele sharing were found at the following loci: D4S2397 and D4S391 (P < 0.05) on 4p, D4S1647 (P < 0.05) on 4q, D7S1802 and D7S1869 (low P = 0.01) on 7p, D9S302 (P = 0.004) on 9q, and D20S604 on 20p and D20S173 on 20q (P < 0.05). In addition, five markers on 7q displayed increased IBD sharing (P = 0.046-0.002). Additional ASP analyses on chromosomes 18 and 21q marker data were performed using disease phenotype models defined previously. On chromosome 18, only D18S40 on 18p and D18S70 on 18q yielded a slight elevation in allele sharing (P = 0.02), implying that the reported linkages in these regions were not confirmed. On chromosome 21q, a cluster of markers within an approximately 9 cM interval: D21S1254, D21S65, D21S1440, and D21S1255 exhibited excess allele sharing (P = 0.041-0.008). Multilocus data on overlapping marker quartets, from D21S1265 to D21S1255, which were consistent with increased IBD sharing (P < 0.01, with a low of 0.0009), overlapped a broad interval of excess allele sharing reported previously, increasing support for a susceptibility locus for bipolar disorder on 21q." [Abstract]

Lovlie R, Berle JO, Stordal E, Steen VM.
The phospholipase C-gamma1 gene (PLCG1) and lithium-responsive bipolar disorder: re-examination of an intronic dinucleotide repeat polymorphism.
Psychiatr Genet 2001 Mar;11(1):41-3
"Twin, family and adoption studies have indicated that genetic susceptibility plays an important role in the etiology of bipolar disorder. Turecki et al. (1998) recently published preliminary evidence suggesting that bipolar patients with an excellent response to lithium treatment have a higher frequency of a specific dinucleotide repeat allele in the phospholipase Cgamma-1 (PLCG1) genomic region. The present work was undertaken to re-examine the finding by Turecki et al. in a sample of Norwegian lithium-treated bipolar patients sub-classified as lithium responders, non-responders, or partial responders/unclassified. The overall distribution of the PLCG1 dinucleotide repeat alleles was not significantly different between different categories of subjects. When analyzed according to presence or absence of different dinucleotide alleles, a PLCG1-8 repeat was more frequent among lithium responders vs controls. In line with Turecki et al., we also noticed a moderately over-representation of the PLCG1-5 repeat among the bipolar patients as compared to the controls." [Abstract]

Turecki G, Grof P, Cavazzoni P, Duffy A, Grof E, Ahrens B, Berghofer A, Muller-Oerlinghausen B, Dvorakova M, Libigerova E, Vojtechovsky M, Zvolsky P, Joober R, Nilsson A, Prochazka H, Licht RW, Rasmussen NA, Schou M, Vestergaard P, Holzinger A, Schumann C, Thau K, Rouleau GA, Alda M.
Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder.
Mol Psychiatry 1998 Nov;3(6):534-8
"Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stabilize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a gamma-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 +/- 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (chi2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined." [Abstract]

OMIM - Online Mendelian Inheritance in Man: PLCG1
[The PLCG1 gene has been located at 20q12-q13.1]

Mundo E, Tharmalingham S, Neves-Pereira M, Dalton EJ, Macciardi F, Parikh SV, Bolonna A, Kerwin RW, Arranz MJ, Makoff AJ, Kennedy JL.
Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.
Mol Psychiatry 2003 Feb;8(2):241-5
"There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated." [Abstract]

Wildenauer DB, Schwab SG, Maier W, Detera-Wadleigh SD.
Do schizophrenia and affective disorder share susceptibility genes?
Schizophr Res 1999 Sep 29;39(2):107-11; discussion 160
"Schizophrenia and affective disorders are relatively common neuropsychiatric diseases with a complex genetic etiology. A multigenic inheritance with variable influence of unknown environmental factors may be involved. Family studies have demonstrated the existence of both phenotypes in the same kindreds, and in certain cases, a transition from one phenotype to another occurs. In addition, intermediate phenotypes such as schizoaffective disorders are found in families with schizophrenia and affective illness. Recent genome and chromosomal scans appear to support these epidemiologic data, since susceptibility regions for both schizophrenia and affective disorders have been found to overlap, on chromosomes 10p13-p12, 13q32, 18p and 22q11-q13. These studies were performed in independently ascertained family samples with index patients afflicted either with schizophrenia or bipolar disorder. Taken together, these findings imply shared loci for schizophrenia and affective disorders among those required for the full expression of the phenotype. Identification and molecular characterization of the genetic components conferring risk to both disorders would impact positively on diagnosis, prevention, and treatment." [Abstract]

Schumacher J, Cichon S, Rietschel M, Nothen MM, Propping P.
[Genetics of bipolar affective disorders. Current status of research for identification of susceptibility genes]
Nervenarzt 2002 Jul;73(7):581-92; quiz 593-4
"Bipolar affective disorder is a highly heritable condition, as evidenced by twin, family, and adoption studies. However, the mode of inheritance is complex and linkage findings have been difficult to replicate. Despite these limitations, consistent linkage findings have emerged for several chromosomes, notably 3p12-p14, 4p16, 10q25-q26, and 12q23-q24. Three additional areas, 13q32-q33, 18p11-q11, and 22q12-q13, have shown linkage in regions that appear to overlap with linkage findings in schizophrenia. These chromosomal regions might harbour genes that contribute to the development of bipolar affective disorder. Recent candidate gene studies include some positive results for the serotonin transporter gene (5-HTT) on 17q11-q12 and the catechol-O-methyltransferase gene (COMT) on 22q11. New methods are being developed for linkage disequilibrium mapping and candidate gene approaches. One can be optimistic that over the next few years bipolar susceptibility genes will be identified." [Abstract]

Pato CN, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Verner A, Hudson TJ, Morley CP, Kennedy JL, Azevedo MH, Daly MJ, Sklar P.
Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11.
Am J Med Genet. 2004 May 15;127B(1):30-4.
"As part of an extensive study in the Portuguese Island population of families with multiple patients suffering from bipolar disorder and schizophrenia, we performed an initial genome-wide scan of 16 extended families with bipolar disorder that identified three regions on chromosomes 2, 11, and 19 with genome-wide suggestive linkage and several other regions, including chromosome 6q, also approached suggestive levels of significance. Dick et al. [2003: Am J Hum Genet 73:107-114] recently reported in a study of 250 families with bipolar disorder a maxLOD score of 3.61 near marker D6S1021 on chromosome 6q. This study replicates this finding having detected a peak NPL = 2.02 (P = 0.025) with the same marker D6S1021(104.7 Mb). Higher-density mapping provided additional support for loci on chromosome 6 including marker D6S1021 with an NPL = 2.59 (P = 0.0068) and peaking at marker D6S1639 (125 Mb) with an NPL = 3.06 (P = 0.0019). A similar pattern was detected with higher-density mapping of chromosome 11 with an NPL = 3.15 (P = 0.0014) at marker D11S1883 (63.1 Mb). Simulations at the density of our fine mapping data indicate that less than 1 scan out of 10 would find two such scores genome-wide in the same scan by chance. Our findings provide additional support for a susceptibility locus for bipolar disorder on 6q, as well as, suggesting the importance of denser scans." [Abstract]

Pato CN, Middleton FA, Gentile KL, Morley CP, Medeiros H, Macedo A, Azevedo MH, Pato MT
Genetic linkage of bipolar disorder to chromosome 6q22 is a consistent finding in Portuguese subpopulations and may generalize to broader populations.
Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):119-21.
We recently reported genome-wide significant linkage to chromosome 6q for bipolar disorder, in a study of 25 Portuguese families, using the Human Mapping Assay Xba 131 (HMA10K). To explore the generalizability of this finding, we reanalyzed our SNP linkage data according to the families' geographic origin. Specifically, the 25 families included 20 families from the Portuguese island collection (PIC; 15 families from the Azores Islands and 5 from the Madeira Islands) and 5 families from continental Portugal. Non-parametric linkage analysis (NPL) was performed as previously described and indicated that each of these subpopulations showed evidence of linkage for the same region. To further address the potential generalizability of these findings to other populations, we have also examined allelic heterozygosity in our subpopulations and in three reference populations (Caucasian, East Asian, and African-American). This analysis indicated that the PIC population is highly correlated to the Caucasian reference population (R = 0.86) for all of chromosome 6. In contrast allelic heterozygosity was more weakly correlated between PIC and both East Asian (R = 0.37) and African-American (R = 0.32) reference populations. Taken together these observations suggest a shared genetic liability among Portuguese populations for bipolar disorder on chromosome 6q, and that the PIC population is likely representative of Caucasians in general. [Abstract]

Schulze TG, Buervenich S, Badner JA, Steele CJ, Detera-Wadleigh SD, Dick D, Foroud T, Cox NJ, MacKinnon DF, Potash JB, Berrettini WH, Byerley W, Coryell W, DePaulo JR, Gershon ES, Kelsoe JR, McInnis MG, Murphy DL, Reich T, Scheftner W, Nurnberger JI, McMahon FJ
Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees.
Biol Psychiatry. 2004 Jul 1;56(1):18-23.
BACKGROUND: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p. METHODS: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed. RESULTS: Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p =.006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r =.26; p <.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p <.0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from.35 to 2.26 on 6p22.2. CONCLUSIONS: These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia. [Abstract]

Lambert D, Middle F, Hamshere ML, Segurado R, Raybould R, Corvin A, Green E, O'mahony E, Nikolov I, Mulcahy T, Haque S, Bort S, Bennett P, Norton N, Owen MJ, Kirov G, Lendon C, Jones L, Jones I, Holmans P, Gill M, Craddock N
Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16-q21, 4q12-q21, 9p21, 10p14-p12 and 18q22.
Mol Psychiatry. 2005 May 17;
Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD=3.30) and D10S197 (LOD=3.18). Multipoint analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16-q21 (MLS=2.61) and 4q12-q21 (MLS=2.38). 6q16-q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male-male pairs. Our scan also provides support for linkage (MLS>/=1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14-p12 and 18q22. [Abstract]

Arai M, Itokawa M, Yamada K, Toyota T, Arai M, Haga S, Ujike H, Sora I, Ikeda K, Yoshikawa T.
Association of neural cell adhesion molecule 1 gene polymorphisms with bipolar affective disorder in Japanese individuals.
Biol Psychiatry. 2004 Apr 15;55(8):804-10.
"BACKGROUND: Although the pathogenesis of mood disorders remains unclear, heritable factors have been shown to be involved. Neural cell adhesion molecule 1 (NCAM1) is known to play important roles in cell migration, neurite growth, axonal guidance, and synaptic plasticity. Disturbance of these neurodevelopmental processes is proposed as one etiology for mood disorder. We therefore undertook genetic analysis of NCAM1 in mood disorders. METHODS: We determined the complete genomic organization of human NCAM1 gene by comparing complementary deoxyribonucleic acid and genomic sequences; mutation screening detected 11 polymorphisms. The genotypic, allelic, and haplotype distributions of these variants were analyzed in unrelated control individuals (n = 357) and patients with bipolar disorder (n = 151) and unipolar disorder (n = 78), all from central Japan. RESULTS: Three single nucleotide polymorphisms, IVS6+32T>C, IVS7+11G>C and IVS12+21C>A, displayed significant associations with bipolar disorder (for allelic associations, nominal p =.04, p =.02, and p =.004, respectively, all p >.05 after Bonferroni corrections). Furthermore, the haplotype located in a linkage disequilibrium block was strongly associated with bipolar disorder (the p value of the most significant three-marker haplotype is.005). CONCLUSIONS: Our results suggest that genetic variations in NCAM1 or nearby genes could confer risks associated with bipolar affective disorder in Japanese individuals." [Abstract]

De bruyn A, Mendelbaum K, Sandkuijl LA, Delvenne V, Hirsch D, Staner L, Mendlewicz J, Van Broeckhoven C.
Nonlinkage of bipolar illness to tyrosine hydroxylase, tyrosinase, and D2 and D4 dopamine receptor genes on chromosome 11.
Am J Psychiatry 1994 Jan;151(1):102-6
"OBJECTIVE: Previous linkage and allelic association studies using DNA polymorphisms, cosegregation of cytogenetic abnormalities with psychiatric illness, and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness. The authors examined linkage in the families of 14 probands with bipolar illness, with the candidate genes tyrosine hydroxylase (TH), D4 dopamine receptor (DRD4) at 11p15, tyrosinase (TYR) at 11q14-q21, and D2 dopamine receptor (DRD2) at 11q22-q23, as well as with the c-Harvey-ras oncogene (HRAS) and insulin gene (INS), both located at 11p15, a region that previously showed linkage to bipolar illness. METHOD: The genetic data were analyzed with both lod score analysis (parametric) and affected-sib-pair analysis (nonparametric); both narrow and broad definitions of the clinical phenotype were used. Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype. RESULTS: Two-point linkage results excluded close linkage of bipolar illness to each candidate gene; negative results were also obtained when the narrow definition of the clinical phenotype was used. Moreover, multipoint linkage analysis of HRAS and INS excluded the 11p15 region encompassing both DRD4 and TH. In agreement with the negative linkage results, affected-sib-pair analysis did not show preferential sharing of marker alleles at any of the candidate genes. CONCLUSIONS: The negative results obtained under different genetic models exclude a frequent role for DRD4, TH, TYR, and DRD2 in the pathogenesis of bipolar illness." [Abstract]

Muglia P, Petronis A, Mundo E, Lander S, Cate T, Kennedy JL.
Dopamine D4 receptor and tyrosine hydroxylase genes in bipolar disorder: evidence for a role of DRD4.
Mol Psychiatry. 2002;7(8):860-6.
"The involvement of the mesocorticolimbic dopamine system in behaviors that are compromised in patients with mood disorder has led to the investigation of dopamine system genes as candidates for bipolar disorder. In particular, the functional VNTRs in the exon III of the dopamine D4 (DRD4) and in intron I of the tyrosine hydroxylase (TH) genes have been investigated in numerous association studies that have produced contrasting results. Likewise, linkage studies in multiplex bipolar families have shown both positive and negative results for markers in close proximity to DRD4 and TH on 11p15.5. We performed a linkage disequilibrium analysis of the DRD4 and TH VNTRs in a sample of 145 nuclear families comprised of DSM-IV bipolar probands and their biological parents. An excess of transmissions and non transmissions was observed for the DRD4 4- and 2-repeat alleles respectively. The biased transmission showed a parent of origin effect (POE) since it was derived almost exclusively from the maternal meiosis (4-repeat allele maternally transmitted 40 times vs 20 times non-transmitted; chi(2) = 6.667; df = 1; P = 0.009; while paternally transmitted 26 times vs 21 times non-transmitted; chi(2) = 0.531; df = 1; P = 0.46). The analysis of TH did not reveal biased transmission of intron I VNTR alleles. Although replication of our study is necessary, the fact that DRD4 exhibit POE and is located on 11p15.5, in close proximity to a cluster of imprinted genes, suggests that genomic imprinting may be operating in bipolar disorder." [Abstract]

McQuillin A, Lawrence J, Curtis D, Kalsi G, Smyth C, Hannesdottir S, Gurling H.
Adjacent genetic markers on chromosome 11p15.5 at or near the tyrosine hydroxylase locus that show population linkage disequilibrium with each other do not show allelic association with bipolar affective disorder.
Psychol Med 1999 Nov;29(6):1449-54
"BACKGROUND: Linkage and association studies have suggested genetic susceptibility to bipolar affective disorder in a region of chromosome 11 around the tyrosine hydroxylase locus. We attempted to test the hypothesis that there was allelic association between polymorphisms around the tyrosine hydroxylase locus and bipolar affective disorder. METHODS: A case-control association study was employed using four polymorphic markers, which span a region of approximately 2 cM across the tyrosine hydroxylase locus. RESULTS: No evidence for allelic association between bipolar affective disorder and any of these markers was found. However, linkage disequilibrium between the markers was detected. CONCLUSIONS: This finding diminishes the probability that genes in this region influence susceptibility to bipolar affective disorder, at least in our sample." [Abstract]

Zandi PP, Willour VL, Huo Y, Chellis J, Potash JB, MacKinnon DF, Simpson SG, McMahon FJ, Gershon E, Reich T, Foroud T, Nurnberger J Jr, DePaulo JR Jr, McInnis MG.
Genome scan of a second wave of NIMH genetics initiative bipolar pedigrees: chromosomes 2, 11, 13, 14, and X.
Am J Med Genet 2003 May 15;119B(1):69-76
"As part of the on-going NIMH Genetics Initiative on Bipolar Disorder, we have ascertained 153 multiplex bipolar pedigrees and genotyped them in two waves. We report here the genome scan results for chromosomes 2, 11, 13, 14, and X in the second wave of 56 families. A total of 354 individuals were genotyped and included in the current analyses, including 5 with schizoaffective/bipolar (SA/BP), 139 with bipolar I disorder (BPI), 41 with bipolar II disorder (BPII), and 43 with recurrent unipolar depression (RUP). Linkage analyses were carried out with multi-point parametric and non-parametric affected relative pair methods using three different definitions of the affected phenotype: (model 1) SA/BP and BPI; (model 2) SA/BP, BPI, and BPII; and (model 3) SA/BP, BPI, BPII, and RUP. The best findings were on 11p15.5 (NPL = 2.96, P = 0.002) and Xp11.3 (NPL = 2.19, P = 0.01). These findings did not reach conventional criteria for significance, but they were located near regions that have been identified in previous genetic studies of bipolar disorder. The relatively modest but consistent findings across studies may suggest that these loci harbor susceptibility genes of modest effect in a subset of families. Large samples such as that being collected by the NIMH Initiative will be necessary to examine the heterogeneity and identify these susceptibility genes." [Abstract]

Buervenich S, Xiang F, Sydow O, Jonsson EG, Sedvall GC, Anvret M, Olson L.
Identification of four novel polymorphisms in the calcitonin/alpha-CGRP (CALCA) gene and an investigation of their possible associations with Parkinson disease, schizophrenia, and manic depression.
Hum Mutat 2001 May;17(5):435-6
"We identified novel polymorphisms in the calcitonin/CGRPalpha (CALCA) gene by direct sequencing of genomic DNA and subsequent genotyping by RFLP (restriction fragment length polymorphism) detection and investigated association with neurological or psychiatric disease. Four novel polymorphic alleles were found: two (g.979G>A and g.4218T>C) represented single nucleotide polymorphisms (SNPs), one consisted of two coupled SNPs in close vicinity to each other (g.1210T>C and g.1214C>G), and one was an intronic 16-bp microdeletion (2919-2934del16). One of the SNPs (g.4218T>C) causes a non-synonymous amino acid change (Leu66Pro) in the third exon, an exon common to both procalcitonin and pro-alpha-CGRP. In a subsequent association study, frequencies of the identified polymorphisms in Parkinson and schizophrenia patients were compared with frequencies in the normal population. No statistically significant association was found in our material. The 16-bp microdeletion polymorphism was present in a family with multiple cases of unipolar or bipolar depressive disorder. Using this polymorphism as marker, cosegregation with the phenotype was observed in the majority of individuals." [Abstract]

OMIM - Online Mendelian Inheritance in Man: CALCA/CGRPalpha
[The CALCA gene has been located at 11p15.2-p15.1]

Edward I. Ginns, Pamela St. Jean, Robert A. Philibert, Marzena Galdzicka, Patricia Damschroder-Williams, Bonnie Thiel, Robert T. Long, Loring J. Ingraham, Harnisha Dalwaldi, Melissa A. Murray, Melissa Ehlert, Sharon Paul, Brian G. Remortel, Ashima P. Patel, Maria C. H. Anderson, Cary Shaio, Elaine Lau, Inna Dymarskaia, Brian M. Martin, Barbara Stubblefield, Kathleen M. Falls, John P. Carulli, Tim P. Keith, Cathy S. J. Fann, Lucy G. Lacy, Cleona R. Allen, Abram M. Hostetter, Robert C. Elston, Nicholas J. Schork, Janice A. Egeland, and Steven M. Paul
A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish
PNAS 95: 15531-15536, December 1998.
"We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5.22 × 10^-4; SIBPAL Pempirical value <3 × 10^-5) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3.29, P = 2.57 × 10^-3; SIBPAL Pempirical value <1 × 10^-3) that are linked to mental health wellness." [Full Text] [Bipolar I]

Dick DM, Foroud T, Edenberg HJ, Miller M, Bowman E, Rau NL, DePaulo JR, McInnis M, Gershon E, McMahon F, Rice JP, Bierut LJ, Reich T, Nurnberger J Jr.
Apparent replication of suggestive linkage on chromosome 16 in the NIMH genetics initiative bipolar pedigrees.
Am J Med Genet 2002 May 8;114(4):407-12
"Analyses of a replication sample of families collected as part of the National Institute of Mental Health (NIMH) Genetics Initiative for bipolar disorder provide further evidence for linkage to a region of chromosome 16. Families who had a bipolar I (BPI) proband and at least one BPI or schizoaffective, bipolar type (SABP) first-degree relative were ascertained for the purpose of identifying genes involved in bipolar affective disorder. A series of hierarchical models of affected status was used in linkage analyses. Initial genetic analyses of chromosomes 3, 5, 15, 16, 17, and 22, completed at Indiana University in 540 subjects from 97 families, suggested evidence of linkage to chromosomes 5, 16, and 22 [Edenberg et al., 1997: Am J Med Genet 74:238-246]. Genotyping was subsequently performed on these chromosomes in a replication sample of 353 individuals from 56 families. Nonparametric linkage analyses were performed using both affected relative and sibling pair methods. Analyses in the new sample on chromosome 16, using the broadest model of affected status, corroborate previously reported suggestive linkage to the marker D16S2619. Combining the initial and replication samples further increased the evidence of linkage to this region, with a peak lod score of 2.8." [Abstract]

Jones I, Gordon-Smith K, Craddock N.
Triplet repeats and bipolar disorder.
Curr Psychiatry Rep 2002 Mar;4(2):134-40
"Anticipation, the phenomenon of a disease becoming more severe or having earlier onset as it is transmitted down the generations, was originally described in families with psychiatric illness but was thought due to ascertainment bias and became forgotten. Interest was rekindled when a number of neurodegenerative disorders that show this phenomenon, were found to be due to a novel form of mutation--unstable triplet repeats showing intergenerational expansion. Some recent studies of anticipation are consistent with its occurrence in bipolar disorder but are still associated with methodological problems making interpretation difficult. A number of case-control studies employing the repeat expansion detection (RED) technique have found longer repeats in bipolar probands but other studies have found no such association. Despite a large number of studies examining the role of various repeat containing candidate genes, a pathogenic triplet repeat has yet to be found for bipolar disorder. It is likely that the controversy surrounding anticipation and the existence of triplet repeats will only finally be resolved with the demonstration of such a mutation in the aetiology of bipolar disorder." [Abstract]

Tsutsumi T, Holmes SE, McInnis MG, Sawa A, Callahan C, DePaulo JR, Ross CA, DeLisi LE, Margolis RL.
Novel CAG/CTG repeat expansion mutations do not contribute to the genetic risk for most cases of bipolar disorder or schizophrenia.
Am J Med Genet. 2004 Jan 1;124B(1):15-9.
"The possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of these diseases. Using the repeat expansion detection (RED) assay, we have systematically examined genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. Our results show that 28% of the probands with schizophrenia and 30% of probands with bipolar disorder have a CAG/CTG repeat in the expanded range, but that each expansion could be explained by one of three nonpathogenic repeat expansions known to exist in the general population. We conclude that novel CAG/CTG repeat expansions are not a common genetic risk factor for bipolar disorder or schizophrenia." [Abstract]

Eichler, Evan E.
Segmental Duplications: What's Missing, Misassigned, and Misassembled---and Should We Care?
Genome Res. 2001 11: 653-656 [Full Text]

Green, Eric D., Chakravarti, Aravinda
The Human Genome Sequence Expedition: Views from the "Base Camp"
Genome Res. 2001 11: 645-651 [Full Text]

GEDDES, JOHN, GOODWIN, GUY
Bipolar disorder: clinical uncertainty, evidence-based medicine and large-scale randomised trials
Br J Psychiatry 2001 178: 191-194
"The increasing use of the methods of evidence-based medicine to keep up-to-date with the research literature highlights the absence of high-quality evidence in many areas in psychiatry." [Full Text]

Jones I, Scourfield J, McCandless F, Craddock N.
Attitudes towards future testing for bipolar disorder susceptibility genes: a preliminary investigation.
J Affect Disord 2002 Sep;71(1-3):189-93
"The discovery of susceptibility genes for the major psychiatric illnesses may lead to the development of presymptomatic and prenatal tests. In a preliminary study we assessed the attitudes of 147 bipolar patients, 90 attendees at their family doctor (GP) and 32 psychiatrists to the possible development of genetic tests for bipolar disorder susceptibility genes. Our results suggest that patients and the public will look favourably on the development of presymptomatic (but not prenatal) testing for bipolar disorder susceptibility genes. Psychiatrists, who will have to administer such tests, appear significantly more cautious." [Abstract]

Prathikanti S, McMahon FJ.
Genome scans for susceptibility genes in bipolar affective disorder.
Ann Med 2001 May;33(4):257-62
"A genome-wide scan for genetic linkage can suggest fresh insights into disease aetiology. However, in the case of complex disorders such as bipolar affective disorder (BPAD), the results of genome-wide scans must be interpreted with caution. We review 10 published and 10 in-progress genome scans of BPAD, encompassing 3536 affected individuals in 1119 pedigrees. We find that ascertainment methods vary widely, with no two studies using identical methods. Sample sizes and marker densities have generally been well below what is now considered adequate, but several in-progress studies are using larger samples and more closely spaced markers. Few findings reach the 'suggestive' threshold, and fewer still reach the 'significant' threshold at genome-wide levels of significance. Strategies for pooling samples or subjecting findings in different samples to meta-analysis are being developed, but differences in ascertainment methods may have a large impact on the uniformity of different samples and hamper efforts at combining data or findings. There is also a need for methods that help define more genetically homogeneous phenotypes, take into account interactions between multiple susceptibility loci, and accommodate additional complexity (eg parent-of-origin effects) in the search for linkage." [Abstract]

Merikangas KR, Chakravarti A, Moldin SO, Araj H, Blangero JC, Burmeister M, Crabbe J Jr, Depaulo JR Jr, Foulks E, Freimer NB, Koretz DS, Lichtenstein W, Mignot E, Reiss AL, Risch NJ, Takahashi JS.
Future of genetics of mood disorders research.
Biol Psychiatry. 2002 Sep 15;52(6):457-77.
This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research. [Abstract]

McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A.
The heritability of bipolar affective disorder and the genetic relationship to unipolar depression.
Arch Gen Psychiatry. 2003 May;60(5):497-502.
"BACKGROUND: Twin studies of bipolar affective disorder (BPD) have either been small or have not used explicit diagnostic criteria. There has been little use of genetic model fitting and no analyses to explore the etiological overlap with unipolar depression (UPD). METHODS: Sixty-seven twin pairs, 30 monozygotic and 37 dizygotic, in which the proband had BPD were ascertained, and lifetime diagnoses were made using DSM-IV criteria. Univariate models were applied to estimate the contribution of additive genetic and environmental effects. Bipolar data were then combined with those from 68 monozygotic and 109 dizygotic pairs in which the proband had UPD. Two models were explored: a classic 2-threshold approach, in which BPD and UPD occupy the same continuum of liability but differ in severity, and a correlated liability model of mania and depression. RESULTS: Heritability of BPD was estimated at 85% (95% confidence interval [CI], 0.73-0.93) using narrow concordance and 89% (95% CI, 0.61-1.0) using broad concordance, with no shared environmental effects detected. A 2-threshold model was an unsatisfactory fit. Fitting a correlated liability model revealed a genetic correlation of 0.65 (95% CI, 0.58-0.75) between mania and depression and a correlation of 0.59 (95% CI, 0.15-0.84) for nonfamilial environment. Approximately 71% of the genetic variance for mania was not shared with depression. CONCLUSIONS: As defined by the DSM-IV, BPD is highly heritable. There are substantial genetic and nonshared environmental correlations between mania and depression, but most of the genetic variance in liability to mania is specific to the manic syndrome." [Abstract]

Faraone SV, Su J, Tsuang MT
A genome-wide scan of symptom dimensions in bipolar disorder pedigrees of adult probands.
J Affect Disord. 2004 Oct;82 Suppl 1S71-8.
Although twin and adoption show bipolar disorder (BP) has a strong genetic component, few chromosomal regions have been consistently implicated by molecular genetic studies. To address this issue, we sought to determine if quantitative dimensions of bipolar disorder symptoms would be useful for detecting genes that underlie the susceptibility to bipolar disorder. Subjects were 520 individuals diagnosed with bipolar I, bipolar II or schizoaffective disorder, bipolar type who had participated in the NIMH genetics initiative for bipolar disorder. We constructed symptom scores from 29 psychiatric symptoms recorded in the Diagnostic Interview for Genetic Studies (DIGS). Principal components factor analysis followed by a varimax rotation was used to extract symptom dimensions. Factor scores were calculated for all genotyped individuals in the sample, regardless of affection status. Heritable factors were used in a variance-components linkage analysis, which utilized the exact likelihoods of allele-sharing identical-by-descent for each pair of relatives within each pedigree. The principal components factor analysis resulted in five independent dimensions: depressed state, psychosis, sleep disturbances, psychomotor acceleration, and irritability. Two factors were significantly heritable: depression (h2=0.53, p<0.001) and irritable vs. euphoric mania (h2=0.35, p=0.03). These were subsequently used in a linkage analysis that resulted in LOD scores of <2.0, which are not statistically significant. The five constructs developed through factor analysis appear to be consistent with previous factor analyses. Notably, only the dimensions associated with the type of mood disturbance showed high heritability, which suggests that careful measurements of depression, euphoria and irritability may be particularly useful in clarifying the genetic etiology of bipolar disorder in future studies. [Abstract]

Duffy A, Grof P.
Psychiatric diagnoses in the context of genetic studies of bipolar disorder.
Bipolar Disord 2001 Dec;3(6):270-5
"Precise definition of the phenotype is an issue of critical importance for the future success of genetic studies of bipolar disorders. So far, an uncertain phenotypic spectrum and genetic heterogeneity are realities that have hampered progress in genetic studies. While recognition of a broader spectrum of related illnesses is important for some applications, for genetic studies a narrow spectrum of illness closely tied to the genotype is paramount. This paper highlights current dilemmas and trends associated with phenotype specification and traces historical approaches. Finally, we explore a number of strategic directions in the diagnostic approach to bipolar disorders that may better serve genetic studies." [Abstract]

Ozer S, Ayhan Y, Ulusahin A.
[The utility of an endophenotype approach in overcoming the difficulties in bipolar and schizophrenia genetics]
Turk Psikiyatri Derg. 2004 Summer;15(2):125-37. [Abstract]

Glahn DC, Bearden CE, Niendam TA, Escamilla MA.
The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder.
Bipolar Disord. 2004 Jun;6(3):171-82. [Abstract]

BLACKWOOD, DOUGLAS H. R., VISSCHER, PETER M., MUIR, WALTER J.
Genetic studies of bipolar affective disorder in large families
Br J Psychiatry 2001 178: 134-136
"Bipolar disorder is likely to be genetically heterogeneous; mutations in one of several independent genes may produce a similar clinical phenotype and different mutations in the same gene may cause a variety of related symptoms. Another possible model is that the clinical symptoms of the affective disorders can be viewed as continuous variables, called quantitative traits, that are produced by the additive or interactive effects of mutations in two or more genes. Under this model, each gene — termed a quantitative trait locus (QTL) — has only a small effect on the trait, and symptoms develop as a result of the cumulative effects of mutations in several genes, probably combined with other internal and external environmental risk factors. In these situations there is also an advantage in studying single large pedigrees where the disease is likely to be caused by a more limited number of interacting genes and environmental factors." [Full Text]

CRADDOCK, NICK, JONES, IAN
Molecular genetics of bipolar disorder
Br J Psychiatry 2001 178: 128-133 [Full Text]

Ewald H, Flint T, Kruse TA, Mors O.
A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22-21, 4p16, 6q14-22, 10q26 and 16p13.3.
Mol Psychiatry 2002;7(7):734-44 [Abstract]

McInnis MG, Dick DM, Willour VL, Avramopoulos D, MacKinnon DF, Simpson SG, Potash JB, Edenberg HJ, Bowman ES, McMahon FJ, Smiley C, Chellis JL, Huo Y, Diggs T, Meyer ET, Miller M, Matteini AT, Rau NL, DePaulo JR, Gershon ES, Badner JA, Rice JP, Goate AM, Detera-Wadleigh SD, Nurnberger JI, Reich T, Zandi PP, Foroud TM.
Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.
Biol Psychiatry. 2003 Dec 1;54(11):1265-73.
"BACKGROUND: In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied. METHODS: Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions. RESULTS: One region, on 16p13, was significant at the genome-wide p <.05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p </=.01). Conditional analysis assuming epistasis identified a significant increase in linkage at four regions. Families linked to 6q24 showed a significant increase in nonparametric logarithms of the odds (NPL) scores at 5q11 and 7q21. Epistasis also was observed between 20p12 and 13q21, and 16p13 and 9q21. CONCLUSIONS:The findings are presented in rank order of nominal significance. Several of these regions have been previously implicated in independent studies of either bipolar disorder or schizophrenia. The strongest finding is at 16p13 at D16S748 with an NPL of 3.3, there is evidence of epistasis between this locus and 9q21. Application of conditional analyses is potentially useful in larger sample collections to identify susceptibility genes of modest influence that may not be identified in a genome-wide scan aimed to identify single gene effects." [Abstract]

Nyegaard M, Borglum AD, Bruun TG, Collier DA, Russ C, Mors O, Ewald H, Kruse TA.
Novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene associated with bipolar affective disorder.
Mol Psychiatry 2002;7(7):745-54
"The somatostatin receptor 5 (SSTR5) gene is a candidate gene for bipolar affective disorder (BPAD) as well as for other neuropsychiatric disorders. The gene is positioned on chromosome 16p13.3, a region that has been implicated by a few linkage studies to potentially harbor a disease susceptibility gene for BPAD. Recent evidence shows that the dopamine D2 receptor (DRD2) and SSTR5 interact physically to form heterodimers with enhanced functional activity. Brain D2 dopamine receptors are one of the major targets of neuroleptic treatments in psychiatric disorders. In this study we systematically screened the promoter and coding region of the SSTR5 gene for genetic variation that could contribute to the development of neuropsychiatric disorders. Eleven novel single nucleotide polymorphisms (SNPs) were identified including four missense SNPs, Leu48Met, Ala52Val, Pro109Ser and Pro335Leu. We carried out an association study of BPAD using 80 Danish cases and 144 control subjects, and replication analysis using 55 British cases and 88 control subjects. For the Danish population, association was suggested between silent SNP G573A and BPAD (P = 0.008). For the British population we found association to BPAD with missense mutation Leu48Met (P = 0.003) and missense mutation Pro335Leu (P = 0.004). The statistical significance of the association was, however, greatly reduced after correcting for multiple testing. When combining genotypes from Leu48Met and Pro335Leu into haplotypes, association to BPAD was found in the British population (P = 0.0007). This haplotype association was not replicated in the Danish population. Our results may indicate that the SSTR5 gene is involved in the etiology of BPAD or may exist in linkage disequilibrium with a susceptibility gene close to SSTR5. However, given the marginal statistical significance and the potential for false-positive results in association studies with candidate genes, further studies are needed to clarify this hypothesis." [Abstract]

On site link: Somatostatin Receptor 5

Ewald H, Mors O, Flint T, Koed K, Eiberg H, Kruse TA.
A possible locus for manic depressive illness on chromosome 16p13.
Psychiatr Genet 1995 Summer;5(2):71-81
"We have previously reported possible evidence for linkage between manic depressive illness and the locus at 16p13.3 encoding the enzyme phosphoglycolate phosphatase (PGP), in the larger of two Danish families. As PGP was not fully informative, 12 additional DNA markers were tested in these families to clarify if a gene involved in the etiology of manic depressive illness might be located on chromosome 16p13. Though not reaching a lod score level of 3.0, the possible presence of a disease gene for manic depressive illness on chromosome 16p13 was still suggested. The evidence for a dominant locus near PGP was weakened. However, when assuming a recessive mode of inheritance and including both families a two-point lod score of 2.52 was found for marker D16S510, and a three-point lod score of 2.65 in both families combined and 2.29 in the large family alone was obtained in the same area. Simulations indicated that lod scores as obtained for several markers in the large family alone, would occur only rarely with an unlinked marker." [Abstract]

Itokawa M, Yamada K, Iwayama-Shigeno Y, Ishitsuka Y, Detera-Wadleigh S, Yoshikawa T.
Genetic analysis of a functional GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in humans.
Neurosci Lett. 2003 Jul 10;345(1):53-6.
"Hypofunction of glutamatergic neurotransmission has been hypothesized to underlie the pathophysiology of bipolar affective disorder, as well as schizophrenia. We examined the role of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene on 16p13.3, a region thought to be linked to bipolar disorder, (1) because in a prior study we identified a functional and polymorphic (GT)n repeat in the 5' regulatory region of the gene, with longer alleles showing lower transcriptional activity and an over representation in schizophrenia, and (2) because of the suggestion of a genetic overlap between affective disorder and schizophrenia. Family-based association tests detected a nominally significant preferential transmission of longer alleles in a panel of 96 multiplex bipolar pedigrees." [Abstract]

Van Broeckhoven C, Verheyen G.
Report of the chromosome 18 workshop.
Am J Med Genet 1999 Jun 18;88(3):263-70
"At the first chromosome 18 workshop held at the 1997 World Congress on Psychiatric Genetics (WCPG) in Santa Fe, NM, several studies were presented that suggested the presence of a bipolar disorder (BP) as well as a schizophrenia (SZ) susceptibility locus on chromosome 18. Although the fact that several independent studies all pointed to a susceptibility locus (or loci) on chromosome 18, the observation that these studies identified nonoverlapping candidate regions was disappointing at least from the viewpoint of molecular genetics aiming at cloning the respective gene(s). Together, the data suggested four possible regions of considerable size that contained a susceptibility gene. At the 1998 WCPG chromosome 18 workshop in Bonn, Germany, less data were submitted and with the exception of a few studies, most data were nonsupportive or negative. Although some refinements were made to the previous candidate loci, overall the picture has not changed in that we are still confronted with the same four potential loci on chromosome 18 for BP and/or SZ, i.e., 18p11.2 and 18q12.1-q12.3 for BP and SZ, and 18q21-q22 and 18q23-qter for BP. So far, no other psychiatric phenotypes show evidence for a susceptibility locus on chromosome 18." [Abstract]

Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE
Genomewide linkage scan for bipolar-disorder susceptibility loci among Ashkenazi Jewish families.
Am J Hum Genet. 2004 Aug;75(2):204-19.
The relatively short history of linkage studies in bipolar disorders (BPs) has produced inconsistent findings. Implicated regions have been large, with reduced levels of significance and modest effect sizes. Both phenotypic and genetic heterogeneity may have contributed to the failure to define risk loci. BP is part of a spectrum of apparently familial affective disorders, which have been organized by severity. Heterogeneity may arise because of insufficient data to define the spectrum boundaries, and, in general, the less-severe disorders are more difficult to diagnose reliably. To address the inherent complexities in detecting BP susceptibility loci, we have used restricted diagnostic classifications and a genetically more homogeneous (Ashkenazi Jewish) family collection to perform a 9-cM autosomal genomewide linkage scan. Although they are genetically more homogeneous, there are no data to suggest that the rate of illness in the Ashkenazim differs from that in other populations. In a genome scan of 41 Ashkenazi pedigrees with a proband affected with bipolar I disorder (BPI) and at least one other member affected with BPI or bipolar II disorder (BPII), we identified four regions suggestive of linkage on chromosomes 1, 3, 11, and 18. Follow-up genotyping showed that the regions on chromosomes 1, 3, and 18 are also suggestive of linkage in a subset of pedigrees limited to relative pairs affected with BPI. Furthermore, our chromosome 18q22 signal (D18S541 and D18S477) overlaps with previous BP findings. This research is being conducted in parallel with our companion study of schizophrenia, in which, by use of an identical approach, we recently reported significant evidence for a schizophrenia susceptibility locus in the Ashkenazim on chromosome 10q22. [Abstract]

Nothen MM, Cichon S, Rohleder H, Hemmer S, Franzek E, Fritze J, Albus M, Borrmann-Hassenbach M, Kreiner R, Weigelt B, Minges J, Lichtermann D, Maier W, Craddock N, Fimmers R, Holler T, Baur MP, Rietschel M, Propping P.
Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families.
Mol Psychiatry 1999 Jan;4(1):76-84
"Previously reported linkage of bipolar affective disorder to DNA markers on chromosome 18 was reexamined in a large sample of German bipolar families. Twenty-three short tandem repeat markers were investigated in 57 families containing 103 individuals with bipolar I disorder (BPI), 26 with bipolar II disorder (BPII), nine with schizoaffective disorder of the bipolar type (SA/BP), and 38 individuals with recurrent unipolar depression (UPR). Evidence for linkage was tested with parametric and non-parametric methods under two definitions of the affected phenotype. Analysis of all 57 families revealed no robust evidence for linkage. Following previous reports we performed separate analyses after subdividing the families with respect to the sex of the transmitting parent. Fourteen families were classified as paternal and 12 families as maternal. In 31 families the parental lineage of transmission of the disease could not be determined ('either' families). Evidence for linkage was obtained for chromosomal region 18p11.2 in the paternal families and for 18q22-23 in the 'either' families. The findings on 18p11.2 and 18q22-23 support prior evidence for susceptibility loci in these regions. The parent-of-origin effect on 18p11.2 is confirmed in our sample. The delineation of characteristics of 'either' families requires further study." [Abstract]

Sevilla D. Detera-Wadleigh, Judith A. Badner, Wade H. Berrettini, Takeo Yoshikawa, Lynn R. Goldin, Gordon Turner, Denise Y. Rollins, Tracy Moses, Alan R. Sanders, Jayaprakash D. Karkera, Lisa E. Esterling, Jin Zeng, Thomas N. Ferraro, Juliet J. Guroff, Diane Kazuba, Mary E. Maxwell, John I. Nurnberger, Jr., and Elliot S. Gershon
A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2
PNAS 96: 5604-5609, 1999.
"Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on 396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0.000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod = 2.67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod = 2.08; P = 0.00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia." [Full Text]

Sjoholt G, Ebstein RP, Lie RT, Berle J, Mallet J, Deleuze JF, Levinson DF, Laurent C, Mujahed M, Bannoura I, Murad I, Molven A, Steen VM.
Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder.
Mol Psychiatry. 2003 Dec 23 [Epub ahead of print].
"Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (-461C>T and -207T>C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder." [Abstract]

OMIM - Online Mendelian Inheritance in Man: IMPA2

Yoshikawa T, Padigaru M, Karkera JD, Sharma M, Berrettini WH, Esterling LE, Detera-Wadleigh SD.
Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2).
Mol Psychiatry 2000 Mar;5(2):165-71
"Recently, we cloned the human myo-inositol monophosphatase 2 (IMPA2) cDNA and established its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder. Because the myo-inositol monophosphatase enzyme has been shown to be inhibited by lithium, an effective therapeutic agent for bipolar disorder, IMPA2 is a plausible positional and functional candidate gene. To permit comprehensive screening for variants we characterized the genomic structure and isolated the potential promoter of IMPA2. The gene was found to encode eight exons spanning;27 kb. The proximal 1-kb 5' flanking region did not contain an obvious TATA box but multiple potential binding sites for Sp1 and consensus motifs for AP2 and other transcription factors were evident. Sequencing of the coding region and splice junctions in unrelated bipolar disorder patients detected novel variants. A missense mutation in exon 2, His76Tyr, was found in one patient. His76 is evolutionarily conserved and replacement with Tyr introduces a potential site for phosphorylation. The other polymorphisms included an RsaI polymorphism, IVS1-15G>A, and a T --> C silent mutation in the third nucleotide of codon 53 in exon 2. By Fisher's exact test the silent mutation showed a trend for association (P = 0.051) with bipolar disorder suggesting that further scrutiny of this gene is warranted." [Abstract]

Sjoholt G, Gulbrandsen AK, Lovlie R, Berle JO, Molven A, Steen VM.
A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients.
Mol Psychiatry 2000 Mar;5(2):172-80
"For several decades, lithium has been the drug of choice in the long-term treatment of manic-depressive illness, but the molecular mechanism(s) mediating its therapeutic effects remain to be determined. The enzyme myo-inositol monophosphatase (IMPase) in the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action. Two genes encoding human IMPases have so far been isolated, namely IMPA1 on chromosome 8q21. 13-21.3 and IMPA2 on chromosome 18p11.2. Interestingly, several studies have indicated the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2. IMPA2 is therefore a candidate for genetic studies on both etiology and lithium treatment of manic-depressive illness. Here we report that the genomic structure of IMPA2 is composed of eight exons, ranging in size from 46 bp to 535 bp. The promoter region contains several Sp1 elements and lacks a TATA-box, features typical for housekeeping genes. By a preliminary polymorphism screening of exons 2-8 in a sample of 23 Norwegian bipolar patients, we have identified nine single nucleotide polymorphisms (SNPs). Seven of the polymorphisms were located in the introns, one was a silent transition in exon 2 (159T>C) and one was a transition in exon 5 (443G>A) resulting in a predicted amino acid substitution (R148Q). Our data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified. IMPA2 is therefore an intriguing candidate gene for future association studies of manic-depressive illness." [Abstract]

Dimitrova A, Milanova V, Krastev S, Nikolov I, Toncheva D, Owen MJ, Kirov G
Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment.
Pharmacogenomics J. 2005;5(1):35-41.
Lithium is the most effective mood-stabilizing drug in the therapy of bipolar affective disorder (BP). It is thought to exert its effect via the phosphatidylinositol signalling system. Myo-inositol monophosphatase 2 (IMPA2) codes for an enzyme in this system that is inhibited by lithium. It is located on 18p11.2, a region implicated as a BP susceptibility locus. We examined eight single-nucleotide polymorphisms (SNPs) identified within this gene for association with BP, using 237 parents-offspring trios and in 174 cases and 170 controls. No SNP showed association with BP. When good responders to lithium treatment were compared with the poor responders, some statistically significant differences emerged for two SNPs; however, the sample became too small to draw definitive conclusions. We cannot find support for the involvement of variation in IMPA2 in susceptibility to bipolar disorder, but the role of this and other genes from the phosphoinositol signalling pathway in predicting response to lithium treatment merits further investigation. [Abstract]

Washizuka S, Kakiuchi C, Mori K, Kunugi H, Tajima O, Akiyama T, Nanko S, Kato T.
Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder.
Am J Med Genet. 2003 Jul 1;120B(1):72-8.
"Linkage of bipolar disorder with 18p11 has been replicated by several investigators. A nuclear-encoded mitochondrial complex I subunit gene, NDUFV2, is one of the candidate genes in this locus, since the possible pathophysiological significance of mitochondrial dysfunction in bipolar disorder has been suggested. The objective of our study was to clarify the association between the NDUFV2 gene and bipolar disorder. We performed the real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) for NDUFV2 mRNA expression in lymphoblastoid cell lines derived from patients with bipolar disorder and healthy controls. We also screened novel polymorphisms using denaturing high performance liquid chromatography (D-HPLC) and PCR-direct sequencing method. Detected five single nucleotide polymorphisms (SNPs) were genotyped. A decrease of the expression level of NDUFV2 gene was found in patients with bipolar I disorder compared with controls (P = 0.006). We also found that the haplotype frequencies of the four polymorphisms in the upstream region of NDUFV2 were significantly different between bipolar disorders and controls (P = 0.0001). Our findings suggest that polymorphisms of the NDUFV2 gene may be one of the genetic risk factors for bipolar disorder." [Abstract]

Washizuka S, Kakiuchi C, Mori K, Tajima O, Akiyama T, Kato T
Expression of mitochondria-related genes in lymphoblastoid cells from patients with bipolar disorder.
Bipolar Disord. 2005 Apr;7(2):146-52.
Objectives: Several studies have suggested mitochondrial abnormality in bipolar disorder. We reported the association of mitochondrial complex I subunit gene, NDUFV2 at 18p11, with bipolar disorder. A decrease in the mRNA expression of this gene was found in patients with bipolar disorder compared with controls. However, it was unclear whether only the NDUFV2 gene exhibited the decreased expression level in bipolar disorder. The aim of this study was to clarify the association of other nuclear-encoded complex I subunit genes and mitochondria-related genes with bipolar disorder. Methods: We quantified the mRNA expression level of five nuclear-encoded mitochondrial complex I subunit genes located at the chromosomal regions linked with bipolar disorder other than NDUFV2, three complex IV subunit genes, and four mitochondrial transcription-related genes using a real-time quantitative reverse transcription polymerase chain reaction method in the lymphoblastoid cell lines from 21 patients with bipolar disorder and 11 controls. Results: Decreased mRNA expression in patients with bipolar I disorder compared with control subjects was found in most of the complex I subunit genes. In addition, decreased expression levels of these genes correlated with that of NDUFV2. No statistically significant alterations of mRNA expression levels were found between bipolar patients and controls among two of three complex IV subunit genes and all transcription-related genes. Conclusions: Our study suggests that the decreased expression of NDUFV2 has a considerable effect on other subunit genes in the mitochondrial respiratory chain and presents further evidence of the biological significance of NDUFV2 in bipolar disorder. [Abstract]

Washizuka S, Iwamoto K, Kazuno AA, Kakiuchi C, Mori K, Kametani M, Yamada K, Kunugi H, Tajima O, Akiyama T, Nanko S, Yoshikawa T, Kato T
Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health pedigrees.
Biol Psychiatry. 2004 Oct 1;56(7):483-9.
BACKGROUND: Linkage with 18p11 is one of the replicated findings in molecular genetics of bipolar disorder. Because mitochondrial dysfunction has been suggested in bipolar disorder, NDUFV2 at 18p11, encoding a subunit of the complex I, reduced nicotinamide adenine dinucleotide (NADH)ubiquinone oxidoreductase, is a candidate gene for this disorder. We previously reported that a polymorphism in the upstream region of NDUFV2, -602G> A, was associated with bipolar disorder in Japanese subjects; however, functional significance of -602G> A was not known. METHODS: We screened the further upstream region of NDUFV2. We performed a case-control study in Japanese patients with bipolar disorder and control subjects and a transmission disequilibrium test in 104 parent and proband trios of the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees. We also performed the promoter assay to examine functional consequence of the -602G> A polymorphism. RESULTS: The -602G> A polymorphism was found to alter the promoter activity. We found that the other haplotype block surrounding -3542G> A was associated with bipolar disorder. The association of the haplotypes consisting of -602G> A and -3542G> A polymorphisms with bipolar disorder was seen both in Japanese case-control samples and NIMH trios. CONCLUSION: Together these findings indicate that the polymorphisms in the promoter region of NDUFV2 are a genetic risk factor for bipolar disorder by affecting promoter activity. [Abstract]

Munakata K, Tanaka M, Mori K, Washizuka S, Yoneda M, Tajima O, Akiyama T, Nanko S, Kunugi H, Tadokoro K, Ozaki N, Inada T, Sakamoto K, Fukunaga T, Iijima Y, Iwata N, Tatsumi M, Yamada K, Yoshikawa T, Kato T
Mitochondrial DNA 3644T-->C mutation associated with bipolar disorder.
Genomics. 2004 Dec;84(6):1041-50.
Mitochondrial dysfunction associated with mutant mitochondrial DNA (mtDNA) has been suggested in bipolar disorder, and comorbidity with neurodegenerative diseases was often noted. We examined the entire sequence of mtDNA in six subjects with bipolar disorder having comorbid somatic symptoms suggestive of mitochondrial disorders and found several uncharacterized homoplasmic nonsynonymous nucleotide substitutions of mtDNA. Of these, 3644C was found in 5 of 199 patients with bipolar disorder but in none of 258 controls (p = 0.015). The association was significant in the extended samples [bipolar disorder, 9/630 (1.43%); controls, 1/734 (0.14%); p = 0.007]. On the other hand, only 5 of 25 family members with this mutation developed bipolar disorder, of which 4 patients with 3644C had comorbid physical symptoms. The 3644T-->C mutation converts amino acid 113, valine, to alanine in the NADH-ubiquinone dehydrogenase subunit I, a subunit of complex I, and 113 valine is well conserved from Drosophila to 61 mammalian species. Using transmitochondrial cybrids, 3644T-->C was shown to decrease mitochondrial membrane potential and complex I activity compared with haplogroup-matched controls. According to human mitochondrial genome polymorphism databases, 3644C was not found in centenarians but was found in 3% of patients with Alzheimer disease and 2% with Parkinson disease. The result of modest functional impairment caused by 3644T-->C suggests that this mutation could increase the risk for bipolar disorder. [Abstract]

Schumacher J, Jamra RA, Freudenberg J, Becker T, Ohlraun S, Otte AC, Tullius M, Kovalenko S, Bogaert AV, Maier W, Rietschel M, Propping P, Nothen MM, Cichon S.
Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder.
Mol Psychiatry. 2004 Feb;9(2):203-7.
"A recent study has suggested that the brain-expressed genes for G72 and D-amino-acid oxidase (DAAO) exert an influence on susceptibility to schizophrenia. Our aim was to replicate this finding in German schizophrenic patients and to assess whether G72 and DAAO might also contribute to the development of bipolar affective disorder. We genotyped seven single-nucleotide polymorphisms (SNPs) in the G72 gene and three in the DAAO gene in 599 patients (299 schizophrenic, 300 bipolar) and 300 controls. At G72, individual SNPs and a four-marker haplotype were associated with schizophrenia. The most significant SNP as well as the haplotype were also associated with bipolar affective disorder (BPAD). DAAO was associated with schizophrenia, but not with BPAD. The association of variation at G72 with schizophrenia as well as BPAD provides molecular support for the hypothesis that these two major psychiatric disorders share some of their etiologic background." [Abstract]

Chen YS, Akula N, Detera-Wadleigh SD, Schulze TG, Thomas J, Potash JB, DePaulo JR, McInnis MG, Cox NJ, McMahon FJ.
Findings in an independent sample support an association between bipolar affective disorder and the G72/G30 locus on chromosome 13q33.
Mol Psychiatry. 2004 Jan;9(1):87-92.
"Markers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reported that single-nucleotide polymorphisms (SNPs) near the G72/G30 locus were associated with BPAD in a sample of 22 pedigrees, and that SNP haplotypes were associated in a second, larger sample of triads. The present study attempts to replicate this finding in an independent case-control sample. Six SNPs near the G72/G30 locus, including the most strongly associated markers in the previous study, were tested in 139 cases and 113 ethnically matched controls. Significant association was detected between BPAD and two adjacent SNPs (smallest P=0.007; global P=0.024). Haplotype analysis produced additional support for association (smallest P=0.004; global P=0.004). Analysis of 31 unlinked microsatellite markers detected no population stratification in the cases or controls studied. Although the associated alleles and haplotypes differ from those previously reported, these new results provide further evidence, in an independent sample, for an association between BPAD and genetic variation in the vicinity of the genes G72 and G30." [Abstract]

Hattori E, Liu C, Badner JA, Bonner TI, Christian SL, Maheshwari M, Detera-Wadleigh SD, Gibbs RA, Gershon ES.
Polymorphisms at the G72/G30 Gene Locus, on 13q33, Are Associated with Bipolar Disorder in Two Independent Pedigree Series.
Am J Hum Genet 2003 Mar 19;72(5) [epub ahead of print]
"Linkage evidence suggests that chromosome 13 (13q32-33) contains susceptibility genes for both bipolar disorder and schizophrenia. Recently, genes called "G72" and "G30" were identified, and polymorphisms of these overlapping genes were reported to be associated with schizophrenia. We studied two series of pedigrees with bipolar disorder: the Clinical Neurogenetics (CNG) pedigrees (in which linkage to illness had been previously reported at 13q32-33), with 83 samples from 22 multiplex families, and the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees, with 474 samples from 152 families. Sixteen single-nucleotide polymorphisms (SNPs) were genotyped at and around the G72/G30 locus, which covered a 157-kb region encompassing the entire complementary DNA sequences of G72 and G30. We performed transmission/disequilibrium testing (TDT) and haplotype analysis, since a linkage-disequilibrium block was present at this gene locus. In the CNG and NIMH data sets, the results of global TDT of the entire haplotype set were significant and consistent (P=.0004 and P=.008, respectively). In the CNG series, the associated genotypes divided the families into those with linkage and those without linkage (partitioned by the linkage evidence). Analysis of the decay of haplotype sharing gave a location estimate that included G72/G30 in its 95% confidence interval. Although statistically significant association was not detected for individual SNPs in the NIMH data set, the same haplotype was consistently overtransmitted in both series. These data suggest that a susceptibility variant for bipolar illness exists in the vicinity of the G72/G30 genes. Taken together with the earlier report, this is the first demonstration of a novel gene(s), discovered through a positional approach, independently associated with both bipolar illness and schizophrenia." [Abstract]

Ilya Chumakov, Marta Blumenfeld, Oxana Guerassimenko, Laurent Cavarec, Marta Palicio, Hadi Abderrahim, Lydie Bougueleret, Caroline Barry, Hiroaki Tanaka, Philippe La Rosa, Anne Puech, Nadia Tahri, Annick Cohen-Akenine, Sylvain Delabrosse, Sébastien Lissarrague, Françoise-Pascaline Picard, Karelle Maurice, Laurent Essioux, Philippe Millasseau, Pascale Grel, Virginie Debailleul, Anne-Marie Simon, Dominique Caterina, Isabelle Dufaure, Kattayoun Malekzadeh, Maria Belova, Jian-Jian Luan, Michel Bouillot, Jean-Luc Sambucy, Gwenael Primas, Martial Saumier, Nadia Boubkiri, Sandrine Martin-Saumier, Myriam Nasroune, Hélène Peixoto, Arnaud Delaye, Virginie Pinchot, Mariam Bastucci, Sophie Guillou, Magali Chevillon, Ricardo Sainz-Fuertes, Said Meguenni, Joan Aurich-Costa, Dorra Cherif, Anne Gimalac, Cornelia Van Duijn, Denis Gauvreau, Gail Ouellette, Isabel Fortier, John Raelson, Tatiana Sherbatich, Nadejda Riazanskaia, Evgeny Rogaev, Peter Raeymaekers, Jeroen Aerssens, Frank Konings, Walter Luyten, Fabio Macciardi, Pak C. Sham, Richard E. Straub, Daniel R. Weinberger, Nadine Cohen, and Daniel Cohen
Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia
PNAS 99: 13675-13680; published online before print as 10.1073/pnas.182412499
"A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia." [Full Text]

Shaw SH, Mroczkowski-Parker Z, Shekhtman T, Alexander M, Remick RA, Sadovnick AD, McElroy SL, Keck PE Jr, Kelsoe JR.
Linkage of a bipolar disorder susceptibility locus to human chromosome 13q32 in a new pedigree series.
Mol Psychiatry. 2003 May;8(5):558-64.
"Bipolar (BP) disorder or manic depressive illness is a major psychiatric disorder for which numerous family, twin and adoption studies support a substantial genetic contribution. Recently, we reported the results of a genome-wide search for BP disorder susceptibility loci in 20 pedigrees. Suggestive evidence for linkage was found in this study at three markers on 13q, representing possibly two peaks separated by 18 cM. We have now collected a second set of 32 pedigrees segregating BP disorder and have tested for evidence of linkage to markers on human chromosome 13q. In this sample, we have replicated the linkage result in 13q32 at D13S154 (lod=2.29), the more proximal of the two original peaks. When all 52 pedigrees were combined, the multipoint maximum lod score peaked approximately 7 cM proximal to D13S154 (lod=3.40), with a second peak occurring between D13S225 and D13S796 (lod=2.58). There have been several other reports of significant linkage to both BP disorder and schizophrenia in this region of chromosome 13. These pedigrees provide additional evidence for at least one locus for BP disorder in 13q32, and are consistent with other reports of a possible genetic overlap between these disorders." [Abstract]

Liu C, Badner JA, Christian SL, Guroff JJ, Detera-Wadleigh SD, Gershon ES.
Fine mapping supports previous linkage evidence for a bipolar disorder susceptibility locus on 13q32.
Am J Med Genet 2001 May 8;105(4):375-80
"A region between D13S71 and D13S274 on 13q32 showed linkage to bipolar disorder (BP) based on a genome scan using markers with an average spacing of approximately 6 cM and an average heterozygosity of approximately 60% [Detera-Wadleigh et al., 1999: Proc Natl Acad Sci USA 96:5604-5609]. In an attempt to confirm this finding and achieve fine mapping of the susceptibility region, nine additional microsatellite markers with average heterozygosity of approximately 86%, located between D13S71 and D13S274, were typed in the same sample. The strongest linkage evidence was detected by multipoint linkage analysis (ASPEX program) around D13S779-D13S225 with maximum LOD score of 3.25 under Affection Status Model II (ASM II; P = 0.0000546). Data from additional nine markers resulted in a decrease of the 95% confidence interval of the linkage region. Association analyses with GASSOC TDT and ASPEX/sib_tdt detect potential linkage disequilibrium with several markers, including D13S280 (ASPEX TDT P = 0.0033, ASM I). These data generated using a higher marker density within the proposed susceptibility region strengthen the validity of our previous findings and suggest a finer localization of the susceptibility gene(s) on 13q32." [Abstract]

Christian SL, McDonough J, Liu Cy CY, Shaikh S, Vlamakis V, Badner JA, Chakravarti A, Gershon ES.
An evaluation of the assembly of an approximately 15-Mb region on human chromosome 13q32-q33 linked to bipolar disorder and schizophrenia.
Genomics 2002 May;79(5):635-56
"Overall, integration of the data from multiple sources is still needed for complete assembly of the 13q32-q33 region." [Abstract]

Badner JA, Gershon ES.
Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.
Mol Psychiatry 2002;7(4):405-11
"Badner and Gershon (2001) presented a technique of meta-analysis of linkage data that could be applied to published genome scans. It combines the reported P-values of individual studies, after correcting each value for the size of the region containing a minimum P-value. Simulations demonstrated that the type I error rate was at least as low as that for a single genome scan and thus genome-wide significance criteria may be applied. Power to detect linkage was at least as high as the power of pooling the data from all the studies. We applied this method to all the published genome scans for bipolar disorder and schizophrenia. We found the strongest evidence for susceptibility loci on 13q (P < 6 x 10(-6)) and 22q (P < 1 x 10(-5)) for bipolar disorder, and on 8p (P < 2 x 10(-4)), 13q (P < 7 x 10(-5)), and 22q (P < 9 x 10(-5)) for schizophrenia." [Abstract]

Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES.
Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor.
Mol Psychiatry. 2002;7(6):579-93.
"Identification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the voltage-dependent calcium channel were associated with bipolar disorder at the P<0.05 level. In view of the large number of hypotheses tested, the two nominally positive associations were then tested in independent populations of bipolar patients and only BDNF remains a potential risk gene. In the replication samples, excess transmission of the valine allele of amino acid 66 of BDNF was observed in the direction of the original result in an additional sample of 334 parent-proband trios (T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene identified 44 additional SNPs. Genotyping eight common SNPs identified three additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD was observed across this region and all adjacent pairwise haplotypes showed excess transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT revealed a global P value of 0.03. A single haplotype was identified that is shared by both the original dataset and the replication sample that is uniquely marked by both the rare A allele of the original SNP and a novel allele 11.5 kb 3'. Therefore, this study of 76 candidate genes has identified BDNF as a potential risk allele that will require additional study to confirm." [Abstract]

OMIM - Online Mendelian Inheritance in Man: BDNF
[The BDNF gene has been located at 11p13]

Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL.
The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study.
Am J Hum Genet. 2002 Sep;71(3):651-5. Epub 2002 Aug 02.
"Bipolar disorder (BP) is a severe psychiatric disease, with a strong genetic component, that affects 1% of the population worldwide and is characterized by recurrent episodes of mania and depression. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of mood disorders, and the aim of the present study was to test for the presence of linkage disequilibrium between two polymorphisms in the BDNF gene and BP in 283 nuclear families. Family-based association test (FBAT) results for the dinucleotide repeat (GT)(N) polymorphism at position -1040 bp showed that allele A3 was preferentially transmitted to the affected individuals (Z=2.035 and P=.042). FBAT results for the val66met SNP showed a significant association for allele G (Z=3.415 and P=.00064). Transmission/disequilibrium test (TDT) haplotype analysis showed a significant result for the 3-G allele combination (P=.000394), suggesting that a DNA variant in the vicinity of the BDNF locus confers susceptibility to BP. Given that there is no direct evidence that either of the polymorphisms we examined alters function, it is unlikely that the actual risk-conferring allele is from these two sites. Rather, the causative site is likely nearby and in linkage disequilibrium with the 3-G haplotype that we have identified." [Abstract]

Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook EH
Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype.
Am J Psychiatry. 2004 Sep;161(9):1698-700.
OBJECTIVE: Transmission of the brain-derived neurotrophic factor (BDNF) Val66 allele in children with a prepubertal and early adolescent bipolar disorder phenotype was examined. METHOD: The prepubertal and early adolescent bipolar disorder phenotype was defined as current DSM-IV bipolar I disorder (manic or mixed phase) with at least one cardinal mania criterion (i.e., euphoria and/or grandiosity) to ensure differentiation from attention deficit hyperactivity disorder. Probands (mean age=10.7 years, SD=2.7) were obtained by consecutive new case ascertainment from designated pediatric and psychiatric venues. Parents and probands were interviewed separately by research nurses who were blind to the probands' diagnoses. Genotyping was done with TaqMan Assay-on-Demand. Analysis was done with the Family Based Association Test program. RESULTS: There were 53 complete, independent trios. The BDNF Val66 allele was preferentially transmitted (Family Based Association Test: chi(2)=6.0, df=1, p=0.014). CONCLUSIONS: This finding in child bipolar disorder is consistent with data for adults with bipolar disorder that show preferential transmission of the Val66 allele. [Abstract]

Skibinska M, Hauser J, Czerski PM, Leszczynska-Rodziewicz A, Kosmowska M, Kapelski P, Slopien A, Zakrzewska M, Rybakowski JK
Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder.
World J Biol Psychiatry. 2004 Oct;5(4):215-20.
Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar disorder. A functional polymorphism Val66Met of BDNF gene was studied in patients with schizophrenia (n=336), bipolar affective disorder (n=352) and healthy controls (n=375). Consensus diagnosis by at least two psychiatrists, according to DSM-IV and ICD-10 criteria, was made for each patient using a structured clinical interview for DSM-IV Axis I disorders (SCID). No association was found between the studied polymorphism and schizophrenia or bipolar affective disorder either for genotype or allele distribution (for genotype: p=0.210 in schizophrenia, p=0.400 in bipolar disorder; for alleles: p=0.260 in schizophrenia, p=0.406 in bipolar disorder). Results were also not significant when analysed by gender. For males genotype distribution and allele frequency were (respectively): p=0.480 and p=0.312 in schizophrenia, p=0.819 and p=0.673 in bipolar affective disorder. Genotype distribution and allele frequency observed in the female group were: p=0.258 for genotypes, p=0.482 for alleles in schizophrenia; p=0.432 for genotypes, p=0.464 for alleles in bipolar affective disorder. A subgroup of schizophrenic (n=62) and bipolar affective patients (n=28) with early age at onset (18 years or younger) was analysed (p=0.328 for genotypes, p=0.253 for alleles in schizophrenia; p=0.032 for genotypes, p=0.858 for alleles in bipolar affective disorder). [Abstract]

Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ.
Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior.
Neuropsychobiology. 2003;48(4):186-9.
"Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, has been implicated in both mood disorders and suicidal behavior. This study has examined the association between the BDNF gene Val66Met polymorphism and mood disorders, age of onset and suicidal behavior in a Chinese sample population. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing depression groups (total, bipolar disorder or major depression) and control subjects. Furthermore, it was not demonstrated that this BDNF polymorphism was associated with age of onset or suicidal history in our mood disorder patients. Based on these results, it seems reasonable to suggest that this polymorphism is unlikely to play a major role in the genetic susceptibility to mood disorders. Given the fact that the positive association between BDNF gene Val66Met polymorphism and bipolar disorder has only been demonstrated for a Caucasian population but not for a Japanese analog or our Chinese sample, it appears likely that this association is ethnicity dependent." [Abstract]

Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, Sinclair M, Crombie C, Walker N, St Clair DM
BDNF gene is a risk factor for schizophrenia in a Scottish population.
Mol Psychiatry. 2005 Feb;10(2):208-12.
Schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P = 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (P < 1 x 10(-8)) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried. [Abstract]

Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T, Sakamoto K, Fukunaga T, Inada T, Suzuki T, Iwata N, Ozaki N, Yamada K, Yoshikawa T
No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study.
Biol Psychiatry. 2004 Sep 1;56(5):376-8.
BACKGROUND: Two previous studies reported a significant association between a missense polymorphism (Val66Met) in the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder; however, contradictory negative results have also been reported, necessitating further investigation. METHODS: We organized a multicenter study of a relatively large sample of 519 patients with bipolar disorder (according to DSM-IV criteria) and 588 control subjects matched for gender, age, and ethnicity (Japanese). Genotyping was done by polymerase chain reaction-based restriction fragment length polymorphism or direct sequencing. RESULTS: The genotype distributions and allele frequencies were similar among the patients and control subjects. Even if the possible relationships of the polymorphism with several clinical variables (i.e., bipolar I or II, presence of psychotic features, family history, and age of onset) were examined, no variable was related to the polymorphism. CONCLUSIONS: The Val66Met polymorphism of the BDNF gene is unrelated to the development or clinical features of bipolar disorder, at least in a Japanese population. [Abstract]

Oswald P, Del-Favero J, Massat I, Souery D, Claes S, Van Broeckhoven C, Mendlewicz J
Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: a Belgian patient-control study.
Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):34-5.
This patient-control association study was conducted to investigate a possible association of two single nucleotide polymorphisms (SNPs), g.11757C > G and g.196G > A, in the brain-derived neurotrophic factor (BDNF) with bipolar affective disorder (BPAD). Two hundred seventy-five individuals of Belgian origin (at least two generations of Belgian ancestors) were genotyped (112 BPAD and 163 controls). No significant differences were found in the frequency of genotypes and alleles of g.196G > A (P = 0.37 and 0.94, respectively) and g.11757C > G (P = 0.49 and 0.59, respectively) between controls and BPAD patients. An haplotype analysis revealed no difference between patients and controls (P = 0.44). We failed to replicate previous findings implicating BDNF in the aetiology of BPAD. However, BDNF remains an interesting target for future genetic studies and should be tested in prospective pharmacogenetic therapeutic trials. [Abstract]

Lachman, HM;Kelsoe, JR;Remick, RA;Sadovnick, AD;Rapaport, MH;Lin, M;Pazur, BA;Roe, AMA;Saito, T;Papolos, DF
Linkage studies suggest a possible locus for bipolar disorder near the velo-cardio-facial syndrome region on chromosome 22
AMERICAN JOURNAL OF MEDICAL GENETICS 74: (2) 121-128 APR 18 1997
Velo-cardio-facial syndrome (VCFS) is a congenital anomaly characterized by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities, that results from a microdeletion of chromosome 22q11. An increased prevalence of psychiatric illness has been observed, with both schizophrenia and bipolar disorder commonly being diagnosed. For these reasons, the VCFS region is an interesting candidate region for bipolar disorder. We examined this region in 17 bipolar families from three populations: 13 families from the general North American population (University of California, San Diego/University of British Columbia, UCSD/UBC), three larger families from New York, and a portion of Old Order Amish pedigree 110. Three microsatellite markers spanning 13 cM around the VCFS region were genotyped in all the families. A maximum lod score of 2.51 was obtained in the UCSD/UBC families under a dominant model at D22S303. In the combined family set, maximum lod scores of 1.68 and 1.28 were obtained at this marker under dominant and recessive models, respectively. [Abstract]

Hashimoto R, Okada T, Kato T, Kosuga A, Tatsumi M, Kamijima K, Kunugi H
The breakpoint cluster region gene on chromosome 22q11 is associated with bipolar disorder.
Biol Psychiatry. 2005 May 15;57(10):1097-102.
BACKGROUND: Although the pathogenesis of bipolar disorder remains unclear, heritable factors have been shown to be involved. The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies. The BCR gene encodes a Rho GTPase activating protein, which is known to play important roles in neurite growth and axonal guidance. METHODS: We examined patients with bipolar disorder (n = 171), major depressive disorder (n = 329) and controls (n = 351) in Japanese ethnicity for genetic association using eleven single nucleotide polymorphisms (SNPs), including a missense one (A2387G; N796S), in the genomic region of BCR. RESULTS: Significant allelic associations with bipolar disorder were observed for three SNPs, and associations with bipolar II disorder were observed in ten SNPs including N796S SNP (bipolar disorder, p = .0054; bipolar II disorder p = .0014). There was a significant association with major depression in six SNPs. S796 allele carriers were in excess in bipolar II patients (p = .0046, odds ratio = 3.1, 95% CI 1.53-8.76). Furthermore, we found a stronger evidence for association with bipolar II disorder in a multi-marker haplotype analysis (p = .0002). CONCLUSIONS: Our results suggest that genetic variations in the BCR gene could confer susceptibility to bipolar disorder and major depressive disorder. [Abstract]

Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faedda G, Goldberg R, Kucherlapati R, Papolos DF.
Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome.
Am J Med Genet 1996 Sep 20;67(5):468-72
"Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder." [Abstract]

Kirov G, Murphy KC, Arranz MJ, Jones I, McCandles F, Kunugi H, Murray RM, McGuffin P, Collier DA, Owen MJ, Craddock N.
Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder.
Mol Psychiatry 1998 Jul;3(4):342-5 [Abstract]

Papolos DF, Veit S, Faedda GL, Saito T, Lachman HM.
Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele.
Mol Psychiatry 1998 Jul;3(4):346-9 [Abstract]

OMIM - Online Mendelian Inheritance in Man: COMT
[Catechol-O-methyltransferase has been located at 22q11.2]

Rotondo, Alessandro, Mazzanti, Chiara, Dell'Osso, Liliana, Rucci, Paola, Sullivan, Patrick, Bouanani, Siham, Gonnelli, Chiara, Goldman, David, Cassano, Giovanni B.
Catechol O-Methyltransferase, Serotonin Transporter, and Tryptophan Hydroxylase Gene Polymorphisms in Bipolar Disorder Patients With and Without Comorbid Panic Disorder
Am J Psychiatry 2002 159: 23-29
"OBJECTIVE: Genetic epidemiologic and clinical data suggest that comorbid panic disorder may define a subtype of bipolar disorder. Comorbid panic disorder might thereby influence the strength of association between bipolar disorder and genes that have been implicated in bipolar disorder on the basis of their function in monoamine neurotransmission and previously reported linkage results. Polymorphic markers at catechol O-methyltransferase (COMT), serotonin transporter (5-HTT), and tryptophan hydroxylase (TPH) genes were analyzed in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. METHOD: Unrelated subjects of Italian descent meeting DSM-III-R criteria for lifetime bipolar disorder (N=111), with (N=49) or without (N=62) comorbid lifetime panic disorder, were compared to 127 healthy subjects. DNA was extracted from blood leukocytes. The frequencies of COMT Val158Met, 5-HTTLPR, and TPH IVS7+218C>A polymorphisms were determined. Genotype and allele frequency comparisons between affected (bipolar disorder, bipolar disorder without panic disorder, or bipolar disorder with panic disorder) and unaffected individuals were carried out with chi-square tests or Fisher’s exact tests. RESULTS: Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT Met158 and the short 5-HTTLPR alleles and genotypes. The differences in the frequencies of the TPH IVS7+218A alleles and genotypes approached statistical significance. CONCLUSIONS: The findings support the hypothesis that comorbid panic disorder identifies a genetic subtype of bipolar disorder and suggest a role for COMT and 5-HTT in vulnerability to these disorders." [Abstract]

Lai TJ, Wu CY, Tsai HW, Lin YM, Sun HS
Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1) and association with bipolar affective disorder in Taiwan.
BMC Med Genet. 2005 Mar 31;6(1):14.
BACKGROUND: Disturbances in serotonin neurotransmission are implicated in the etiology of many psychiatric disorders, including bipolar affective disorder (BPD). The tryptophan hydroxylase gene (TPH), which codes for the enzyme catalyzing the rate-limiting step in serotonin biosynthetic pathway, is one of the leading candidate genes for psychiatric and behavioral disorders. In a preliminary study, we found that TPH1 intron7 A218C polymorphism was associated with BPD. This study was designed to investigate sequence variants of the TPH1 gene in Taiwanese and to test whether the TPH1 gene is a susceptibility factor for the BPD. METHODS: Using a systematic approach, we have searched the exons and promoter region of the TPH1 gene for sequence variants in Taiwanese Han and have identified five variants, A-1067G, G-347T, T3804A, C27224T, and A27237G. These five variants plus another five taken from the literature and a public database were examined for an association in 108 BPD patients and 103 controls; no association was detected for any of the 10 variants. RESULTS: Haplotype constructions using these 10 SNPs showed that the 3 most common haplotypes in both patients and controls were identical. One of the fourth common haplotype in the patient group (i.e. GGGAGACCCA) was unique and showed a trend of significance with the disease (P = 0.028). However, the significance was abolished after Bonferroni correction thus suggesting the association is weak. In addition, three haplotype-tagged SNPs (htSNPs) were selected to represent all haplotypes with frequencies larger than 2% in the Taiwanese Han population. The defined TPH1 htSNPs significantly reduce the marker number for haplotype analysis thus provides useful information for future association studies in our population. CONCLUSION: Results of this study did not support the role of TPH1 gene in BPD etiology. As the current studies found the TPH1 gene under investigation belongs to the peripheral serotonin system and may link to a cardiac dysfunction phenotype, a second TPH gene that functions predominantly in the brain (i.e., nTPH or TPH2) should be the target for the future association study. [Abstract]

Mannisto, Pekka T., Kaakkola, Seppo
Catechol-O-methyltransferase (COMT): Biochemistry, Molecular Biology, Pharmacology, and Clinical Efficacy of the New Selective COMT Inhibitors
Pharmacol Rev 1999 51: 593-628 [Full Text]

Graf WD, Unis AS, Yates CM, Sulzbacher S, Dinulos MB, Jack RM, Dugaw KA, Paddock MN, Parson WW.
Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism.
Neurology 2001 Aug 14;57(3):410-6
"In patients with the 22q11.2 deletion syndrome and low-activity COMT, controlled studies of pharmacologic agents that decrease catecholamine production, block presynaptic catecholamine storage, or enhance S-adenosylmethionine, the cosubstrate of COMT, are warranted." [Abstract]

Kealey C, Roche S, Claffey E, McKeon P
Linkage and candidate gene analysis of 14q22-24 in bipolar disorder: support for GCHI as a novel susceptibility gene.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jul 5;136(1):75-80.
Using a collection of Irish sib-pair nuclear families, we previously obtained modest evidence of linkage implicating 14q22-24 in bipolar disorder (BPD). To follow-up on this preliminary finding, an extended linkage analysis was performed which employed thirteen microsatellite markers, spanning a total distance of 85 cM on 14q. Effectively, P-values <0.05 were observed for a region extending over 41.88 cM, with the marker D14S281 displaying a peak multipoint non-parametric lod (NPL) score of 2.72 and an associated P-value of 0.003. Support for this finding was also obtained from flanking markers indicating excess allele sharing at 14q22-24 in Irish bipolar sib-pairs. A web-based candidate gene search of 14q22-24 resulted in the selection of GTP cyclohydrolase I (GCHI), located 200 kb 3' of D14S281, as the best plausible candidate gene for involvement in BPD. GCHI is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH(4)), a natural cofactor for tyrosine and tryptophan hydroxylases. These enzymes play an essential role in the biosynthesis of various hormones and neurotransmitters such as dopamine, noradrenaline, adrenaline, and serotonin. Numerous studies have also suggested that the clinical symptoms of depression might be related to a deficiency of BH(4). An association study between BPD and a novel single nucleotide polymorphism (SNP) in GCHI (G to A at position -959 bp, upstream of the ATG codon), is also presented here. This study revealed that the variant A allele is preferentially transmitted to BPI probands (chi(2) = 4.54, P = 0.033) suggesting that variants within GCHI may contribute to BPD in the Irish population. [Abstract]

Ophoff RA, Escamilla MA, Service SK, Spesny M, Meshi DB, Poon W, Molina J, Fournier E, Gallegos A, Mathews C, Neylan T, Batki SL, Roche E, Ramirez M, Silva S, De Mille MC, Dong P, Leon PE, Reus VI, Sandkuijl LA, Freimer NB.
Genomewide linkage disequilibrium mapping of severe bipolar disorder in a population isolate.
Am J Hum Genet 2002 Sep;71(3):565-74
"Genomewide association studies may offer the best promise for genetic mapping of complex traits. Such studies in outbred populations require very densely spaced single-nucleotide polymorphisms. In recently founded population isolates, however, extensive linkage disequilibrium (LD) may make these studies feasible with currently available sets of short tandem repeat markers, spaced at intervals as large as a few centimorgans. We report the results of a genomewide association study of severe bipolar disorder (BP-I), using patients from the isolated population of the central valley of Costa Rica. We observed LD with BP-I on several chromosomes; the most striking results were in proximal 8p, a region that has previously shown linkage to schizophrenia. This region could be important for severe psychiatric disorders, rather than for a specific phenotype." [Abstract]

Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M, Walker MT, Woodburn K, Sharp CM, Wright AF, Shibasaki Y, St Clair DM, Porteous DJ, Muir WJ.
A locus for bipolar affective disorder on chromosome 4p.
Nat Genet 1996 Apr;12(4):427-30
"We have carried out a linkage study in twelve bipolar families. In a single family a genome search employing 193 markers indicated linkage on chromosome 4p where the marker D4S394 generated a two-point lod score of 4.1 under a dominant model of inheritance. Three point analyses with neighbouring markers gave a maximum lod score of 4.8. Eleven other bipolar families were typed using D4S394 and in all families combined there was evidence of linkage with heterogeneity with a maximum two-point lod score of 4.1 (theta = 0, alpha = 0.35)." [Abstract] [4p16]

Ewald H, Degn B, Mors O, Kruse TA.
Support for the possible locus on chromosome 4p16 for bipolar affective disorder.
Mol Psychiatry 1998 Sep;3(5):442-8
"Significant evidence for linkage between bipolar affective disorder and markers on chromosome 4p16 has been reported in Scottish families. Linkage analyses using 16 DNA markers covering more than 50 cM from chromosome 4pter-4p12, including candidate genes encoding the dopamine D5 receptor and an adrenergic receptor (2C), were performed in two Danish families with bipolar affective disorder. Assuming homogeneity in the two families, the highest lod score found in the two-point linkage analyses was 2.00 at 0.03 recombination fraction for D4S394, i.e. the marker which also was most significant in the original Scottish study. Simulation showed that such a lod score would only occur six out of 10,000 times with an unlinked marker. Though the present study thus replicates the Scottish findings according to the criteria suggested by Lander and Kruglyak, caution is warranted as the mode of inheritance which yielded the highest lod score in the two studies was different. Final proof of a disease locus in the Scottish and our study has to await the identification of a DNA sequence of functional significance for bipolar disorder." [Abstract]

Kennedy JL, Macciardi FM.
Chromosome 4 workshop.
Psychiatr Genet 1998 Summer;8(2):67-71
"The largest cluster of positive results, considering both bipolar and schizophrenia, occurs in the 4p region that includes D4S394 and DRD5. Four groups report at least weakly positive linkage analyses this region for bipolar disorder, and two groups find weak positive allelic association with schizophrenia in the region, although at separate markers. On the other hand, at least five groups do not find evidence for linkage of bipolar disorder to this area of 4p. The pattern on 4q is less clear, with a mixture of negative and small positive results in either bipolar or schizophrenia families. Additional allelic association and TDT studies of 4p markers in bipolar disorder and in schizophrenia might be able to narrow the focus of the 4p investigations." [Abstract]

Blair IP, Badenhop RF, Scimone A, Moses MJ, Kerr NP, Donald JA, Mitchell PB, Schofield PR
Association analysis of transcripts from the bipolar susceptibility locus on chromosome 4q35, exclusion of a pathogenic role for eight positional candidate genes.
Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):56-9.
Bipolar affective disorder is a major psychiatric illness with a population prevalence of up to 1.6%. The disorder is genetically complex. To date, no specific gene or DNA sequence variation that predisposes to the disorder has been described, however several susceptibility loci have been proposed through genetic linkage analysis. We previously identified one such susceptibility locus on chromosome 4q35, and refined the interval harboring this susceptibility gene to a size that is amenable to positional cloning. Several independent studies have now been described that support the presence of a susceptibility gene at this locus. In order to identify candidate genes for testing association with bipolar disorder, we previously established a comprehensive transcript map that encompasses the chromosome 4q35 susceptibility locus implicated in our linkage analysis. In this study, we have selected full-length genes from the transcript map and determined the genomic structure of each gene. We identified informative, intragenic single nucleotide polymorphisms (SNPs) by screening all exons and flanking intron sequences in affected individuals from seven bipolar pedigrees that we previously reported as showing evidence for linkage to chromosome 4q35. Analysis of these SNPs was then extended to our unrelated bipolar case-control cohort to test for association with the disorder. Our data suggests that all genes analyzed can be excluded from direct involvement in the disorder. We have therefore, excluded approximately half the genes within the chromosome 4q35 candidate interval from playing a direct pathogenic role in bipolar disorder. [Abstract]

Willour VL, Zandi PP, Huo Y, Diggs TL, Chellis JL, MacKinnon DF, Simpson SG, McMahon FJ, Potash JB, Gershon ES, Reich T, Foroud T, Nurnberger JI Jr, DePaulo JR Jr, McInnis MG.
Genome scan of the fifty-six bipolar pedigrees from the NIMH genetics initiative replication sample: chromosomes 4, 7, 9, 18, 19, 20, and 21.
Am J Med Genet. 2003 Aug 15;121B(1):21-7.
"The NIMH genetics initiative on bipolar disorder was established to collect uniformly ascertained bipolar pedigrees for genetic studies. In 1997, the four participating sites published a genome scan on the initial set of 97 bipolar pedigrees. Fifty-six additional bipolar pedigrees have now been ascertained and evaluated. This replication pedigree set contains 354 genotyped subjects, including 139 bipolar I (BPI) subjects, five schizoaffective bipolar type SA/BP subjects, 41 bipolar II (BPII) subjects, and 43 recurrent unipolar (RUP) depression subjects. Our site has recently genotyped the replication study bipolar pedigrees using 107 microsatellite markers from chromosomes 4, 7, 9, 18, 19, 20, and 21. We are now reporting parametric and nonparametric linkage results from this effort. Multipoint nonparametric linkage analysis produced three candidate regions with allele sharing LOD scores >/= 1.0. The linkage signal on 4q35 peaked between markers D4S3335 and D4S2390 with an allele sharing LOD score of 2.49. This finding exceeds standard criteria for suggestive linkage. Two additional loci approach suggestive linkage levels: the 4q32 finding had its maximum near marker D4S1629 with an allele sharing LOD score of 2.16, and the 20p12 finding peaked at D20S162 with an allele sharing LOD score of 1.82. Multipoint parametric linkage analysis produced similar findings. When we combined the genotype data from the original and the replication pedigree sets, 20p12 yielded a nonparametric LOD score of 2.38, which exceeds standard criteria for suggestive linkage, and a corresponding parametric HLOD score of 2.98. The combined analysis did not provide further support for linkage to 4q32 and 4q35." [Abstract]

Pekkarinen, P, Terwilliger, J, Bredbacka, PE, Lonnqvist, J, Peltonen, L
Evidence of a predisposing locus to bipolar disorder on Xq24-q27.1 in an extended Finnish pedigree
Genome Res. 1995 5: 105-115
"An X-chromosomal predisposing locus to manic-depressive illness has been suggested since 1969 on the basis of the cosegregation of this trait in some families with phenotypic markers, such as color blindness, the glucose-6-phosphate dehydrogenase deficiency, and the coagulation factor IX deficiency. However, the conclusive evidence and the exact location of the putative X-chromosomal locus have remained controversial. We report here a linkage between DNA markers near the coagulation factor IX gene and bipolar disorder in an extended pedigree rising from the genetically isolated population of Finland. A distinct chromosomal haplotype covering a 20-cM region on Xq24-q27.1 could be demonstrated to segregate with bipolar disorder. These findings should encourage research groups to study extended family materials with Xq24- q27.1 markers to finally resolve the question of the X-chromosomal linkage of bipolar disorder." [Abstract]

Ekholm JM, Pekkarinen P, Pajukanta P, Kieseppa T, Partonen T, Paunio T, Varilo T, Perola M, Lonnqvist J, Peltonen L.
Bipolar disorder susceptibility region on Xq24-q27.1 in Finnish families.
Mol Psychiatry 2002;7(5):453-9
"We have earlier reported significant evidence of linkage for BPD to chromosome Xq24-q27.1 in an extended pedigree from the late settlement region of the genetically isolated population of Finland. Further, we established a distinct chromosomal haplotype covering a 19 cM region on Xq24-q27.1 co-segregating with the disorder. Here, we have further analyzed this X-chromosomal region using a denser marker map and monitored X-chromosomal haplotypes in a study sample of 41 Finnish bipolar families. Only a fraction of the families provided any evidence of linkage to this region, suggesting that a relatively rare gene predisposing to BPD is enriched in this linked pedigree. The genome-wide scan for BPD predisposing loci in this large pedigree indicated that this particular X-chromosomal region provides the best evidence of linkage genome-wide, suggesting an X-chromosomal gene with a major role for the genetic predisposition of BPD in this family." [Abstract]

Liu J, Juo SH, Dewan A, Grunn A, Tong X, Brito M, Park N, Loth JE, Kanyas K, Lerer B, Endicott J, Penchaszadeh G, Knowles JA, Ott J, Gilliam TC, Baron M.
Evidence for a putative bipolar disorder locus on 2p13-16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21-24, 13q32, 14q21 and 17q11-12.
Mol Psychiatry 2003 Mar;8(3):333-42
"Bipolar disorder (BP) is a severe and common psychiatric disorder characterized by extreme mood swings. Family, twin and adoption studies strongly support a genetic component. The mode of inheritance is complex and likely involves multiple, as yet unidentified genes. To identify susceptibility loci, we conducted a genome-wide scan with 343 microsatellite markers in one of the largest, well-characterized pedigree samples assembled to date (373 individuals in 40 pedigrees). To increase power to detect linkage, scan statistics were used to examine the logarithm of odds (lod) scores based on evidence at adjacent chromosomal loci. This analysis yielded significant evidence of linkage (genome-wide P&<0.05) for markers on 2p13-16. Standard linkage analysis was also supportive of linkage to 2p13-16 (lod=3.20), and identified several other interesting regions: 4q31 (lod=3.16), 7q34 (lod=2.78), 8q13 (lod=2.06), 9q31 (lod=2.07), 10q24 (lod=2.79), 13q32 (lod=2.2), 14q21 (lod=2.36) and 17q11-12 (lod=2.75). In this systematic, large-scale study, we identified novel putative loci for BP (on 2p13-16, 8q13 and 14q21) and found support for previously proposed loci (on 4q31, 7q34, 9q31, 10q21-24, 13q32 and 17q11-12). Two of the regions implicated in our study, 2p13-14 and 13q32, have also been linked to schizophrenia, suggesting that the two disorders may have susceptibility genes in common." [Abstract]

Macqueen GM, Hajek T, Alda M
The phenotypes of bipolar disorder: relevance for genetic investigations.
Mol Psychiatry. 2005 Jun 21;
The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. [Abstract]

Park N, Juo SH, Cheng R, Liu J, Loth JE, Lilliston B, Nee J, Grunn A, Kanyas K, Lerer B, Endicott J, Gilliam TC, Baron M
Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia.
Mol Psychiatry. 2004 Dec;9(12):1091-9.
The low-to-moderate resolution of linkage analysis in complex traits has underscored the need to identify disease phenotypes with presumed genetic homogeneity. Bipolar disorder (BP) accompanied by psychosis (psychotic BP) may be one such phenotype. We previously reported a genome-wide screen in a large bipolar pedigree sample. In this follow-up study, we reclassified the disease phenotype based on the presence or absence of psychotic features and subgrouped pedigrees according to familial load of psychosis. Evidence for significant linkage to psychotic BP (genome-wide P<0.05) was obtained on chromosomes 9q31 (lod=3.55) and 8p21 (lod=3.46). Several other sites were supportive of linkage, including 5q33 (lod=1.78), 6q21 (lod=1.81), 8p12 (lod=2.06), 8q24 (lod=2.01), 13q32 (lod=1.96), 15q26 (lod=1.96), 17p12 (lod=2.42), 18q21 (lod=2.4), and 20q13 (lod=1.98). For most loci, the highest lod scores, including those with genome-wide significance (at 9q31 and 8p21), occurred in the subgroup of families with the largest concentration of psychotic individuals (> or =3 in a family). Interestingly, all regions but six--5q33, 6q21, 8p21, 8q24, 13q32 and 18q21--appear to be novel; namely, they did not show notable linkage to BP in other genome scans, which did not employ psychosis for disease classification. Also of interest is possible overlap with schizophrenia, another major psychotic disorder: seven of the regions presumed linked in this study--5q, 6q, 8p, 13q, 15q, 17p, and 18q--are also implicated in schizophrenia, as are 2p13 and 10q26, which showed more modest support for linkage. Our results suggest that BP in conjunction with psychosis is a potentially useful phenotype that may: (1) expedite the detection of susceptibility loci for BP and (2) cast light on the genetic relationship between BP and schizophrenia. [Abstract]

Green EK, Raybould R, Macgregor S, Gordon-Smith K, Heron J, Hyde S, Grozeva D, Hamshere M, Williams N, Owen MJ, O'Donovan MC, Jones L, Jones I, Kirov G, Craddock N
Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder.
Arch Gen Psychiatry. 2005 Jun;62(6):642-8.
CONTEXT: Family and twin data suggest that, in addition to susceptibility genes specific for bipolar disorder or schizophrenia, genes exist that contribute to susceptibility across the traditional kraepelinian divide. Several studies have provided evidence that variation at the neuregulin 1 (NRG1) gene on chromosome 8p12 influences susceptibility to schizophrenia. The most consistent finding has been that one particular haplotype (the "core" haplotype) is overrepresented in cases compared with control subjects. OBJECTIVE: To investigate the possible role of NRG1 in bipolar disorder. DESIGN: Genetic case-control association analysis. SETTING: Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. PARTICIPANTS: Five hundred twenty-nine patients with DSM-IV bipolar I disorder and 1011 controls from the United Kingdom (100% white). METHODS: We genotyped the markers constituting the NRG1 core haplotype in cases and controls and reanalyzed our existing data from 573 DSM-IV schizophrenia cases with this larger set of controls. RESULTS: We found a significant difference in haplotype distribution between bipolar cases and controls globally (P = .003) and specifically for the core haplotype. Frequencies were 10.2% for bipolar cases and 7.8% for controls (effect size, as measured by odds ratio [OR], 1.37; 95% confidence interval [CI], 1.03-1.80; P = .04). The effect size in our bipolar sample was similar to that in our schizophrenia sample (OR, 1.22; 95% CI, 0.92-1.61). In the bipolar cases with predominantly mood-incongruent psychotic features (n = 193), the effect was greater (OR, 1.71; 95% CI, 1.29-2.59; P = .009), as was the case in the subset of schizophrenia cases (n = 27) who had experienced mania (OR, 1.64; 95% CI, 0.54-5.01). CONCLUSIONS: Our findings suggest that neuregulin 1 plays a role in influencing susceptibility to bipolar disorder and schizophrenia and that it may exert a specific effect in the subset of functional psychosis that has manic and mood-incongruent psychotic features. [Abstract]

Lohoff FW, Ferraro TN, McNabb L, Schwebel C, Dahl JP, Doyle GA, Buono RJ, Berrettini WH
No association between common variations in the neuronal nicotinic acetylcholine receptor alpha2 subunit gene (CHRNA2) and bipolar I disorder.
Psychiatry Res. 2005 Jul 2;
The neuronal nicotinic acetylcholine receptor alpha2 subunit gene (CHRNA2) maps to the bipolar susceptibility locus on chromosome 8p21-22. Given the biological role of the neuronal nicotinic acetylcholine receptors and the substantial comorbidity of nicotine dependence in psychiatric disorders, the CHRNA2 gene is a plausible candidate gene for bipolar disorder (BPD). We tested the hypothesis that variations in the CHRNA2 gene confer susceptibility to bipolar I disorder in a case-control association study. Genotypes of one amino acid substitution polymorphism (Ala125Thr) and five non-coding variations across the CHRNA2 gene were obtained from 345 unrelated bipolar I patients and 273 control samples. Genotypes and allele frequencies were compared between groups using chi-square contingency analysis. Linkage disequilibrium (LD) between markers was calculated, and estimated haplotype frequencies were compared between groups. We observed no statitistically significant difference in genotype and allele frequencies for all six variations between bipolar patients and controls, but we did demonstrate strong LD throughout the gene. Haplotype analysis showed that no combinations of alleles were associated with illness. Our results suggest that common variations in the CHRNA2 gene are unlikely to confer susceptibility to BPD in this sample. Further studies are required to elucidate the susceptibility locus for BPD on chromosome 8p21-22. [Abstract]

Venken T, Claes S, Sluijs S, Paterson AD, van Duijn C, Adolfsson R, Del-Favero J, Van Broeckhoven C
Genomewide scan for affective disorder susceptibility Loci in families of a northern Swedish isolated population.
Am J Hum Genet. 2005 Feb;76(2):237-48.
We analyzed nine multigenerational families with ascertained affective spectrum disorders in northern Sweden's geographically isolated population of Vasterbotten. This northern Swedish population, which originated from a limited number of early settlers approximately 8,000 years ago, is genetically more homogeneous than outbred populations. In a genomewide linkage analysis, we identified three chromosomal loci with multipoint LOD scores (MPLOD) >/=2 at 9q31.1-q34.1 (MPLOD 3.24), 6q22.2-q24.2 (MPLOD 2.48), and 2q33-q36 (MPLOD 2.26) under a recessive affected-only model. Follow-up genotyping with application of a 2-cM density simple-tandem-repeat (STR) map confirmed linkage at 9q31.1-q34.1 (MPLOD 3.22), 6q23-q24 (MPLOD 3.25), and 2q33-q36 (MPLOD 2.2). In an initial analysis aimed at identification of the underlying susceptibility genes, we focused our attention on the 9q locus. We fine mapped this region at a 200-kb STR density, with the result of an MPLOD of 3.70. Genealogical studies showed that three families linked to chromosome 9q descended from common founder couples approximately 10 generations ago. In this approximately 10-generation pedigree, a common ancestral haplotype was inherited by the patients, which reduced the 9q candidate region to 1.6 Mb. Further, the shared haplotype was observed in 4.2% of patients with bipolar disorder with alternating episodes of depression and mania, but it was not observed in control individuals in a patient-control sample from the Vasterbotten isolate. These results suggest a susceptibility locus on 9q31-q33 for affective disorder in this common ancestral region. [Abstract]

Abou Jamra R, Sircar I, Becker T, Freudenberg-Hua Y, Ohlraun S, Freudenberg J, Brockschmidt F, Schulze TG, Gross M, Spira F, Deschner M, Schmäl C, Maier W, Propping P, Rietschel M, Cichon S, Nöthen MM, Schumacher J
A family-based and case-control association study of trace amine receptor genes on chromosome 6q23 in bipolar affective disorder.
Mol Psychiatry. 2005 Jul;10(7):618-20. [Abstract]

Dick DM, Foroud T, Flury L, Bowman ES, Miller MJ, Rau NL, Moe PR, Samavedy N, El-Mallakh R, Manji H, Glitz DA, Meyer ET, Smiley C, Hahn R, Widmark C, McKinney R, Sutton L, Ballas C, Grice D, Berrettini W, Byerley W, Coryell W, DePaulo R, MacKinnon DF, Gershon ES, Kelsoe JR, McMahon FJ, McInnis M, Murphy DL, Reich T, Scheftner W, Nurnberger JI Jr.
Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative.
Am J Hum Genet. 2003 Jul;73(1):107-14. Epub 2003 May 27.
"We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder." [Abstract]

Badenhop RF, Moses MJ, Scimone A, Mitchell PB, Ewen-White KR, Rosso A, Donald JA, Adams LJ, Schofield PR.
A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19.
Mol Psychiatry 2002;7(8):851-9
"Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13 pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P = 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23." [Abstract]

Radhakrishna U, Senol S, Herken H, Gucuyener K, Gehrig C, Blouin JL, Akarsu NA, Antonarakis SE.
An apparently dominant bipolar affective disorder (BPAD) locus on chromosome 20p11.2-q11.2 in a large Turkish pedigree.
Eur J Hum Genet 2001 Jan;9(1):39-44
"Bipolar affective disorder (BPAD), also known as manic-depressive illness, is a common complex, polygenic disorder characterised by recurrent cyclic episodes of mania and depression. Family, twin, and adoption studies strongly suggest a genetic predisposition/susceptibility to BPAD, but no genes have yet been identified. We studied a large Turkish pedigree, with an apparently autosomal dominant BPAD, which contained 13 affected individuals. The age of onset ranged from 15-40 with a mean of 25 years. The phenotypes consisted of recurrent manic and major depressive episodes, including suicidal attempts; there was usually full remission with lithium treatment. A genome-wide linkage analysis using a dominant mode of inheritance showed strong evidence for a BPAD susceptibility locus on chromosome 20p11.2-q11.2. The highest 2-point lod score of 4.34 at theta = 0 was obtained with markers D20S604, D20S470, D20S836 and D20S838 using a dominant model with full penetrance. Haplotype analysis enabled the mapping of the BPAD locus in this family between markers D20S186 and D20S109, to a region of approximately 42 cM." [Abstract]

Muller DJ, Schulze TG, Jahnes E, Cichon S, Krauss H, Kesper K, Held T, Maier W, Propping P, Nothen MM, Rietschel M.
Association between a polymorphism in the pseudoautosomal X-linked gene SYBL1 and bipolar affective disorder.
Am J Med Genet 2002 Jan 8;114(1):74-8
"In the past decade, several chromosomal regions have been analyzed for linkage with bipolar affective disorder (BPAD). There have been conflicting results regarding the involvement of X-chromosomal regions in harboring susceptibility genes for BPAD. Recently, a new candidate gene (SYBL1) for BPAD has been described on Xq28. SYBL1, which maps to the Xq pseudoautosomal region (PAR), encodes a member of the synaptobrevin family of proteins involved in synaptic vesicle docking, exocytosis, and membrane transport. A subsequent case-control association study, including 110 US-American patients with BPAD and 119 unrelated controls, investigated a potential etiological role of a novel polymorphism (G-->C transversion) in a regulatory region of the SYBL1 gene. In this analysis, the C allele showed a statistical trend to be more frequent in males with BPAD than in respective controls (P=0.06). This finding prompted us to verify whether a similar effect was also present in a larger German sample of 164 unrelated patients with BPAD (148 patients with BP I disorder, 16 patients with BP II disorder) and 267 controls. We observed a significantly increased frequency of genotypes homozygous for the C allele in females with BPAD in comparison with controls (P=0.017). Thus, our data strengthen the role of the SYBL1 gene as a candidate gene for BPAD." [Abstract]

Saito T, Parsia S, Papolos DF, Lachman HM.
Analysis of the pseudoautosomal X-linked gene SYBL1 in bipolar affective disorder: description of a new candidate allele for psychiatric disorders.
Am J Med Genet 2000 Jun 12;96(3):317-23
"The absence of father-to-son transmission has been observed in a subset of families with bipolar disorder (BPD), suggestive of a susceptibility gene on the sex-linked portion of the X chromosome. This is supported by some genetic linkage studies that have provided evidence for a susceptibility locus near Xq28. We have analyzed one candidate gene on Xq28, SYBL1, which maps to the Xq pseudoautosomal region (PAR). SYBL1 encodes a member of the synaptobrevin family of proteins that is involved in synaptic vesicle docking and membrane transport. Genes in the PAR generally escape X-chromosome inactivation and have an active homolog on the Y chromosome, which would result in an increase in same-sex concordance in paternal transmitted traits. However, SYBL1 is neither expressed on the Y chromosome nor the inactive X chromosome and would therefore be expected to show typical sex-linked transmission. We have screened SYBL1 for mutations that could be tested as candidate alleles in the development of BPD. Following single-strand conformation polymorphism (SSCP) analysis and DNA sequencing, four single nucleotide polymorphisms were detected: a silent mutation at codon 108, two intron mutations without any obvious biological significance, and a G-->C transversion in the polypyrimidine tract at the 3' splice acceptor site preceding exon 8. This polymorphism, which creates a perfect 16/16 stretch of pyrimidines, was analyzed in 110 patients with BPD not selected for sex-linked transmission and 119 control subjects. The results show a statistical trend toward an increase in the frequency of the C allele in males with BPD but not females. Males: chi(2) = 3.46, 1 df, p =.06; Females: chi(2) =.20, 1 df, p =.66." [Abstract]

Bocchetta A, Piccardi MP, Martinelli V, Quesada G, Del Zompo M.
Maternal inheritance of manic depression in hemizygotes for the G6PD-Mediterranean mutation. Indirect evidence for Xq28 transmission in Sardinia.
Psychiatr Genet. 1999 Jun;9(2):63-8.
"Both X-linkage and a parent-of-origin effect have been hypothesized in manic-depressive disorder. We have previously shown an allelic association between X-linked G6PD deficiency and manic depression in Mediterranean populations. To test both X-linkage and a parent-of-origin effect in manic depression further, we have studied 274 Sardinian manic-depressive probands and their parents. Excess of maternal transmission (P = 0.005) of major affective disorder was found in male probands carrying the G6PD-Mediterranean mutation. Our results provide indirect molecular support for an association between manic depression and the Xq28 chromosome region in Sardinia. Further studies on Xq28 using tests of allelic association and transmission disequilibrium with multiple DNA markers are required, to clarify the nature of the association we have found. Our study cannot implicate or exclude a direct role for G6PD deficiency in the aetiology of manic depression." [Abstract]

Bocchetta A.
Psychotic mania in glucose-6-phosphate-dehydrogenase-deficient subjects.
Ann Gen Hosp Psychiatry. 2003 Jun 13;2(1):6.
"BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been associated with acute psychosis, catatonic schizophrenia, and bipolar disorders by previous inconclusive reports. A particularly disproportionate rate of enzyme deficiency was found in manic schizoaffective patients from 662 lithium patients surveyed in Sardinia. The purpose of this study was to describe clinical characteristics which may be potentially associated with G6PD deficiency. METHODS: Characteristics of episodes, course of illness, family pattern of illness, laboratory tests, and treatment response of 29 G6PD-deficient subjects with a Research Diagnostic Criteria diagnosis of manic schizoaffective disorder were abstracted from available records. RESULTS: The most peculiar pattern was that of acute recurrent psychotic manic episodes, mostly characterized by loosening of associations, agitation, catatonic symptoms, and/or transient confusion, concurrent hyperbilirubinemia, positive psychiatric family history, and partial response to long-term lithium treatment. CONCLUSIONS: A relationship between psychiatric disorder and G6PD deficiency is to be searched in the bipolar spectrum, particularly among patients with a history of acute episodes with psychotic and/or catatonic symptoms or with transient confusion." [Full Text]

Thomson PA, Wray NR, Thomson AM, Dunbar DR, Grassie MA, Condie A, Walker MT, Smith DJ, Pulford DJ, Muir W, Blackwood DH, Porteous DJ
Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor.
Mol Psychiatry. 2004 Sep 28;
GPR50: is an orphan G protein-coupled receptor (GPCR) located on Xq28, a region previously implicated in multiple genetic studies of bipolar affective disorder (BPAD). Allele frequencies of three polymorphisms in GPR50 were compared in case-control studies between subjects with BPAD (264), major depressive disorder (MDD) (226), or schizophrenia (SCZ) (263) and ethnically matched controls (562). Significant associations were found between an insertion/deletion polymorphism in exon 2 and both BPAD (P=0.0070), and MDD (P=0.011) with increased risk associated with the deletion variant (GPR50(Delta502-505)). When the analysis was restricted to female subjects, the associations with BPAD and MDD increased in significance (P=0.00023 and P=0.0064, respectively). Two other single-nucleotide polymorphisms (SNPs) tested within this gene showed associations between: the female MDD group and an SNP in exon 2 (P=0.0096); and female SCZ and an intronic SNP (P=0.0014). No association was detected in males with either MDD, BPAD or SCZ. These results suggest that GPR50(Delta502-505), or a variant in tight linkage disequilibrium with this polymorphism, is a sex-specific risk factor for susceptibility to bipolar disorder, and that other variants in the gene may be sex-specific risk factors in the development of schizophrenia.Molecular Psychiatry advance online publication, 28 September 2004; doi:10.1038/sj.mp.4001593 [Abstract]

Oruc L, Verheyen GR, Furac I, Jakovljevic M, Ivezic S, Raeymaekers P, Van Broeckhoven C.
Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder.
Am J Med Genet 1997 Sep 19;74(5):504-6
"We selected 42 patients with bipolar disorder type I (BPI) and 40 healthy controls for genetic analysis of DNA polymorphisms in the serotonin receptor 2c (5-HTR2c) and serotonin transporter (5-HTT) genes. No significant associations were found in the total patient sample. However, when the individuals were divided according to gender, trends for association with both polymorphisms (P = 0.051 for 5-HTR2c and P = 0.049 for 5-HTT) in female patients were observed. These results suggest that variations in these genes may be responsible for a minor increase in susceptibility for bipolar disorder in women." [Abstract]

Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S, Del Favero J, Dikeos DG, Kaneva R, Lilli R, Massat I, Milanova V, Muir W, Noethen M, Oruc L, Petrova T, Papadimitriou GN, Rietschel M, Serretti A, Souery D, Van Gestel S, Van Broeckhoven C, Mendlewicz J.
Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder.
Mol Psychiatry 2001 Sep;6(5):579-85
"We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),5 in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, 2 = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (2 = 7.34, df 1, P = 0.006) and BP (2 = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder." [Full Text]

Gutierrez B, Fananas L, Arranz MJ, Valles V, Guillamat R, van Os J, Collier D.
Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder.
Neurosci Lett 1996 Jul 5;212(1):65- 7
"These results suggest that the ser23 allele may increase susceptibility to bipolar affective disorder in women." [Abstract]

OMIM - Online Mendelian Inheritance in Man: 5-HT2C Receptor
[5-HT2C has been located at Xq24]

On site link: 5-HT2C and Bipolar Affective Disorder

OMIM - Online Mendelian Inheritance in Man: 5-HTT
[The serotonin transporter has been located at 17q11.1-q12]

On site link: Serotonin Transporter (5-HTT) Research

Bellivier F, Leroux M, Henry C, Rayah F, Rouillon F, Laplanche JL, Leboyer M.
Serotonin transporter gene polymorphism influences age at onset in patients with bipolar affective disorder.
Neurosci Lett 2002 Dec 6;334(1):17-20
"Serotonin transporter (SLC6A4) gene polymorphism is associated with several behavioral and psychiatric traits. In bipolar affective disorder, two polymorphisms of the SLC6A4 gene, a variable number of tandem repeats in the second intron and a 44 bp insertion/deletion in the serotonin transporter gene linked polymorphic region (5-HTTLPR), have been extensively studied. The findings are conflicting possibly because of the heterogeneity of bipolar disorder. Early-onset bipolar disorder appears to be clinically and genetically more homogeneous and was recently suggested to be associated with the 5-HTTLPR polymorphism. We tested the association between two polymorphisms of the SLC6A4 gene and age at onset (AAO) in a sample of bipolar patients. For both SLC6A4 gene polymorphisms, AAO of subjects with different genotypes were compared. SLC6A4 genotype distributions of different AAO groups were also compared. The variable number of tandem repeats (VNTR) polymorphism significantly influences the AAO but the serotonin transporter gene linked polymorphic region (5-HTTLPR) polymorphism did not. Patients carrying at least one VNTR STin2.12 allele began their illness later whereas patients carrying the 'ss' genotype tended to begin their illness earlier. Differential sampling procedures may influence the proportion of AAO subgroups in a given association study, and therefore these results may explain the conflicting results obtained in studies of the association between the SLC6A4 gene polymorphism and bipolar affective disorder (BPAD)." [Abstract]

Anguelova M, Benkelfat C, Turecki G.
A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders.
Mol Psychiatry. 2003 Jun;8(6):574-91.
"The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR=1.14, CI: 1.03-1.26, P=0.015 for the promoter locus (N=3467) and Mantel-Haenszel Weighted odds ratio OR=1.18, CI: 1.05-1.32, P=0.004 for the VNTR locus (N=3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between BD and 5-HTT." [Abstract]

Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT
Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders.
Am J Med Genet B Neuropsychiatr Genet. 2005 Feb 5;133(1):110-5.
Family, twin, and adoption studies show that psychiatric diseases including bipolar disorder (BP) and unipolar disorder (UP) have a substantial genetic component. For these illnesses, both positive and negative associations have been reported for two polymorphisms located in the serotonin transporter gene (5-HTT) on chromosome 17: a 17-base-pair (bp) variable-number tandem-repeat (VNTR) in intron 2 and a 44-bp insertion/deletion in the promoter region. Thus, associations between these 5-HTT polymorphisms and affective disorders remain unclear. The present work investigates these potential associations in meta-analyzes that maximize the power to find associations between each disease and the two 5-HTT polymorphisms. We applied meta-analysis techniques to case-control studies of two 5-HTT polymorphisms and two affective disorders (BP and UP), resulting in four meta-analyzes. For each polymorphism, we assessed the evidence for allelic associations, heterogeneity among studies, the influence of individual studies, and the potential for publication bias. The short allele(s) of the 44-bp insertion/deletion polymorphism showed a significant association for BP (odds ratio (OR) = 1.13, P = 0.001) but not UP. For the 17-bp VNTR, an increase in the number of tandem repeats had no significant association with any of the disorders. The small but significant effects of the 44-bp insertion/deletion polymorphism for BP is consistent with being one of many genes that contributes to the multi-factorial nature of these psychiatric disorders. [Abstract]

Serretti A, Malitas PN, Mandelli L, Lorenzi C, Ploia C, Alevizos B, Nikolaou C, Boufidou F, Christodoulou GN, Smeraldi E.
Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders.
Pharmacogenomics J. 2004 Apr 27 [Epub ahead of print] [Abstract]

Massat I, Souery D, Del-Favero J, Oruc L, Noethen MM, Blackwood D, Thomson M, Muir W, Papadimitriou GN, Dikeos DG, Kaneva R, Serretti A, Lilli R, Smeraldi E, Jakovljevic M, Folnegovic V, Rietschel M, Milanova V, Valente F, Van Broeckhoven C, Mendlewicz J.
Excess of allele1 for alpha3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study.
Mol Psychiatry 2002;7(2):201-7
"The available data from preclinical and pharmacological studies on the role of gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in brain GABAergic system activity contributes to the vulnerability to bipolar affective disorders (BPAD). Moreover, the localization of the alpha3 subunit GABA receptor GABRA3 gene on the Xq28, a region of interest in certain forms of bipolar illness, suggests that GABRA3 may be a candidate gene in BPAD. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentric case-control sample, matched for sex and ethnogeographical origin. Allele and genotype (in females) frequencies were compared in 185 BPAD patients and 370 controls. A significant increase of genotype 1-1 was observed in BPAD females compared to controls (P=0.0004). Furthermore, when considering recessivity of allele 1 (females with genotype 1-1 and males carrying allele 1), results were even more significant (P= 0.00002). Our findings suggest that the GABRA3 polymorphism may confer susceptibility to or may be in linkage disequilibrium with another gene involved in the genetic etiology of BPAD." [Abstract]

Bailer U, Leisch F, Meszaros K, Lenzinger E, Willinger U, Strobl R, Heiden A, Gebhardt C, Doge E, Fuchs K, Sieghart W, Kasper S, Hornik K, Aschauer HN.
Genome scan for susceptibility loci for schizophrenia and bipolar disorder.
Biol Psychiatry. 2002 Jul 1;52(1):40-52.
"BACKGROUND: Despite the widely accepted view that schizophrenia and bipolar disorder represent independent illnesses and modes of inheritance, some data in the literature suggest that the diseases may share some genetic susceptibility. The objective of our analyses was to search for vulnerability loci for the two disorders. METHODS: A genomewide map of 388 microsatellite DNA markers was genotyped in five schizophrenia and three bipolar disorder Austrian families. Linkage analyses was used to compute the usual parametric logarithm of the likelihood of linkage (LOD) scores and nonparametric linkage analysis (NPL scores Z(all)) was used to assess the pattern of allele sharing at each marker locus relative to the presence of the disease (GENEHUNTER). Affected status was defined as severe affective disorder or schizophrenia. RESULTS: Across the genome, p values associated with NPL scores resulted in evidence (i.e., p <.0007) for linkage at marker D3S1265 on chromosome 3q (NPL score Z (all) = 3.74, p =.0003). Two other markers (on 3q and 6q) showed p values of <.01. CONCLUSIONS: We detected a potential susceptibility locus for bipolar disorder and schizophrenia on chromosome 3q, which has not been reported previously. The possibility of a false positive result has to be taken into account. Our data suggest shared loci for schizophrenia and bipolar affective disorders and are consistent with the continuum model of psychosis." [Abstract]

Schosser A, Fuchs K, Leisch F, Bailer U, Meszaros K, Lenzinger E, Willinger U, Strobl R, Heiden A, Gebhardt C, Kasper S, Sieghart W, Hornik K, Aschauer HN.
Possible linkage of schizophrenia and bipolar affective disorder to chromosome 3q29; a follow-up.
J Psychiatr Res. 2004 May-Jun;38(3):357-64.
"The present linkage study is a follow-up within the chromosome 3q29 region in schizophrenia and bipolar affective disorder families, based on our recently published genome scan, resulting in evidence for linkage of both disorders to this region (marker D3S1265: NPL [non parametric lod] score Z(all)=3.74, P=0.003). Using the same family sample (five pedigrees with schizophrenic index patients and three pedigrees with index bipolar disorder patients N=86; 50 of them were available for genotyping), genotyping of eight additional markers close to D3S1265 was done. Five of those new markers (three centromeric and two telomeric of D3S1265) spanning 4.14 cM (centiMorgan) could be used for statistical analyses ("new markers"). Moreover, marker D3S1265, genotyped within the published genome scan, was used for additional calculations. Linkage analysis was performed using the GENEHUNTER program version 2.1r3. Within newly genotyped markers the highest NPL score Z(all) observed was 1.93296 with the telomeric SNP (single nucleotide polymorphism) rs1835669, corresponding to P=0.032166. Statistical analysis including D3S1265, located in between the newly genotyped markers, resulted in a peak NPL score Z(all)=4.00179 with marker D3S1265, that is P=0.000128. Doing subset analyses of the bipolar disorder and schizophrenia families separately with new markers and D3S1265, linkage signals arose substantially from bipolar disorder families, with contribution from schizophrenia families, too. The results of our follow-up study support our previous linkage finding of schizophrenia and bipolar affective disorder to chromosome 3q29." [Abstract]

Permana PA, Mott DM.
Genetic analysis of human type 1 protein phosphatase inhibitor 2 in insulin-resistant Pima Indians.
Genomics. 1997 Apr 1;41(1):110-4.
"We determined that the authentic PPP1R2 gene is located on chromosome 3q29 and consists of six exons. The previously reported homologue of PPP1R2 on chromosome 5 is identified as an intronless pseudogene." [Abstract]

Foster JD, Pananusorn B, Cervinski MA, Holden HE, Vaughan RA.
Dopamine transporters are dephosphorylated in striatal homogenates and in vitro by protein phosphatase 1.
Brain Res Mol Brain Res. 2003 Jan 31;110(1):100-8.
"Dopamine transporters (DATs) undergo increased phosphorylation upon treatment of striatal tissue or cultured cells with protein kinase C activators and protein phosphatase inhibitors. Phosphorylation conditions also lead to reductions in dopamine transport activity, which may function to regulate synaptic dopamine levels and control the extent and duration of dopaminergic signaling. Treatment of rat striatal tissue with okadaic acid (OA), a broad-spectrum protein phosphatase inhibitor, produces apparent maximal increases in DAT phosphorylation, suggesting that dephosphorylation is a crucial regulator of the DAT phosphorylation state. We used a combination of endogenous and in vitro approaches to identify the phosphatase(s) responsible for this activity. In homogenates prepared from (32)PO(4)-labeled rat striatal slices, OA inhibited DAT dephosphorylation with an IC(50) of 40 nM, a dose most compatible with inhibition of protein phosphatase 1 (PP1). Dephosphorylation of DAT in striatal homogenates was also inhibited by PP1 inhibitor 2, while little effect was produced by protein phosphatase 2A inhibitor 1. In vitro dephosphorylation assays showed substantial removal of (32)PO(4) from DATs by PP1 but not by protein phosphatase 2A, protein phosphatase 2B, or protein tyrosine phosphatase, and this effect was blocked by OA, verifying that the (32)PO(4) loss from DAT was due to dephosphorylation. These results demonstrate that DAT is a direct substrate for PP1 in vitro and suggest that PP1 is a major DAT phosphatase in rat striatum." [Abstract]

Cichon S, Schmidt-Wolf G, Schumacher J, Muller DJ, Hurter M, Schulze TG, Albus M, Borrmann-Hassenbach M, Franzek E, Lanczik M, Fritze J, Kreiner R, Weigelt B, Minges J, Lichtermann D, Lerer B, Kanyas K, Strauch K, Windemuth C, Baur MP, Wienker TF, Maier W, Rietschel M, Propping P, Nothen MM.
A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25--q26.
Mol Psychiatry 2001 May;6(3):342-9
"In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26." [Abstract]

Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I, Tsujita T, Okazaki Y, Nanko S, Kunugi H, Sasaki T, Kato T.
Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder.
Nat Genet. 2003 Aug 31 [Epub ahead of print].
"The pathophysiology of bipolar disorder is still unclear, although family, twin and linkage studies implicate genetic factors. Here we identified XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, as contributing to the genetic risk factor for bipolar disorder. Using DNA microarray analysis of lymphoblastoid cells derived from two pairs of twins discordant with respect to the illness, we found downregulated expression of genes related to ER stress response in both affected twins. A polymorphism (-116C-->G) in the promoter region of XBP1, affecting the putative binding site of XBP1, was significantly more common in Japanese patients (odds ratio = 4.6) and overtransmitted to affected offspring in trio samples of the NIMH Bipolar Disorder Genetics Initiative. XBP1-dependent transcription activity of the -116G allele was lower than that of the -116C allele, and in the cells with the G allele, induction of XBP1 expression after ER stress was markedly reduced. Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1. These results indicate that the -116C-->G polymorphism in XBP1 causes an impairment of its positive feedback system and increases the risk of bipolar disorder." [Abstract]

Masui T, Hashimoto R, Kusumi I, Suzuki K, Tanaka T, Nakagawa S, Kunugi H, Koyama T
A possible association between the -116C/G single nucleotide polymorphism of the XBP1 gene and lithium prophylaxis in bipolar disorder.
Int J Neuropsychopharmacol. 2005 Jun 1;1-6.
Bipolar disorder (BPD) is a severe, chronic, and life-threatening illness, and its pathogenesis remains unclear. Recently, a functional polymorphism (-116C/G) of the X-box binding protein 1 (XBP1) gene was reported to be a genetic risk factor for BPD. Moreover, the endoplasmic reticulum stress responses were impaired in cultured lymphocytes from BPD patients with the -116G allele and only valproate rescued such impairment among three major mood stabilizers. In this context, we hypothesized that BPD patients with different genotypes respond differently to mood stabilizers. We investigated the association between the -116C/G polymorphism of the XBP1 gene and lithium response in Japanese patients with BPD. We found that lithium treatment is more effective among BPD patients with the -116C allele carrier than in patients homozygous for the -116G allele. The association between the -116C/G polymorphism and clinical efficacy of mood stabilizers should be further investigated in a prospective study with a larger sample. [Abstract]

Hou SJ, Yen FC, Cheng CY, Tsai SJ, Hong CJ
X-box binding protein 1 (XBP1) C--116G polymorphisms in bipolar disorders and age of onset.
Neurosci Lett. 2004 Sep 2;367(2):232-4.
X-box binding protein 1 (XBP1), a critical gene in the endoplasmic reticulum stress response, is located on chromosome 22q12, which has been linked with bipolar disorders in several studies. Recently, associations have been reported between a polymorphism (-116C --> G) in the promoter region of XBP1, and bipolar disorders in both case-control study and family-based association study, however, this finding is not yet confirmed by other research using independent sample populations. To replicate this finding and determine the association between onset age of bipolar disorders and the XBP1 C--116G polymorphism, we investigated the prevalence of this polymorphism in a Chinese population (153 bipolar disorder patients and 174 controls). We were unable, however, to demonstrate a significant association between the C--116G polymorphism and bipolar disorders (P = 0.674 for genotype and P = 0.436 for allele frequency) or age at onset (P = 0.563). Further, no association was demonstrated between this polymorphism and family history in bipolar disorder patients. These negative findings suggest that the XBP1 C--116G polymorphism does not play a major role in the pathogenesis of bipolar disorders in Chinese populations. [Abstract]

Cichon S, Buervenich S, Kirov G, Akula N, Dimitrova A, Green E, Schumacher J, Klopp N, Becker T, Ohlraun S, Schulze TG, Tullius M, Gross MM, Jones L, Krastev S, Nikolov I, Hamshere M, Jones I, Czerski PM, Leszczynska-Rodziewicz A, Kapelski P, Bogaert AV, Illig T, Hauser J, Maier W, Berrettini W, Byerley W, Coryell W, Gershon ES, Kelsoe JR, McInnis MG, Murphy DL, Nurnberger JI, Reich T, Scheftner W, O'Donovan MC, Propping P, Owen MJ, Rietschel M, Nöthen MM, McMahon FJ, Craddock N
Lack of support for a genetic association of the XBP1 promoter polymorphism with bipolar disorder in probands of European origin.
Nat Genet. 2004 Aug;36(8):783-4; author reply 784-5. [Abstract]

Benedetti F, Serretti A, Colombo C, Barbini B, Lorenzi C, Campori E, Smeraldi E.
Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression.
Am J Med Genet. 2003 Nov 15;123B(1):23-6.
"Recent studies showed that a polymorphism (T to C nucleotide substitution) in the 3' flanking region of the human CLOCK gene is associated with diurnal preferences of human healthy subjects, with higher "eveningness" in subjects carrying at least one copy of the C allele. We investigated the possible role of CLOCK gene polymorphism in the regulation of diurnal mood fluctuations during a major depressive episode. Sample (n = 101) was collected, in the context of previously reported trials, among patients affected by bipolar disorder type I, depressive episode without psychotic features, free of psychotropic medications. Perceived mood levels were assessed three times a day with self-administered visual analogue scales. Genotype groups showed no significant difference in diurnal mood fluctuations. When stratifying the sample by including only patients with an adequate period of observation (duration of illness higher than 5 years, n = 69), we post-hoc observed a significantly higher recurrence rate in homozygotes for the C variant, which was almost double than that of the other genotype groups. This preliminary observation leads to hypothesize a role for the CLOCK gene polymorphism in the regulation of long-term illness recurrence in bipolar disorder. Given the post-hoc nature of the finding, replication in independent samples is necessary to confirm it." [Abstract]

Bailer U, Wiesegger G, Leisch F, Fuchs K, Leitner I, Letmaier M, Konstantinidis A, Stastny J, Sieghart W, Hornik K, Mitterauer B, Kasper S, Aschauer HN
No association of clock gene T3111C polymorphism and affective disorders.
Eur Neuropsychopharmacol. 2005 Jan;15(1):51-5.
CLOCK was hypothesised to be related to susceptibility of affective disorders. To test subsamples of affectively disordered patients, we examined age of onset (AoO), numbers of episodes and melancholic type of clinical manifestation. Using PCR and RFLP, we investigated in patients with unipolar depression and bipolar disorder (BP) whether the CLOCK T3111C SNP is associated with affective disorders (n=102) compared to healthy controls (n=103). No differences were found either in genotype or allele frequency distributions of T3111C polymorphism between patients compared to healthy controls (p>0.2). No deviations from Hardy-Weinberg Equilibrium (HWE) were detected either in patients, or healthy controls. Results suggest that there is no association between the T3111C SNP and affective disorders in general. Data of our sample replicate prior findings of Desan et al. [Am. J. Med. Genet. 12 (2000) 418]. Subsamples of patients with high numbers of affective episodes did show some deviations in genotypes (p=0.0585). [Abstract]

Serretti A, Benedetti F, Mandelli L, Lorenzi C, Pirovano A, Colombo C, Smeraldi E.
Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism.
Am J Med Genet. 2003 Aug 15;121B(1):35-8.
"We investigated the possible effect of the 3111T/C CLOCK gene polymorphism on sleep disorders in a sample of 620 patients affected by major depressive disorder (MDD) and bipolar disorder (BP). We detected a significantly higher recurrence of initial (P = 0.0001), middle (P = 0.0009), and early (P = 0.0008) insomnia in homozygotes for the C variant and a similar trend concerning decreased need of sleep in BP (P = 0.0074). Other demographic and clinical features were found not related with CLOCK polymorphisms. This preliminary observation leads to hypothesize a possible involvement of the CLOCK gene polymorphism in the sleep disregulations in MDD and BP." [Abstract]

Faraone SV, Glatt SJ, Su J, Tsuang MT.
Three potential susceptibility loci shown by a genome-wide scan for regions influencing the age at onset of mania.
Am J Psychiatry. 2004 Apr;161(4):625-30.
"OBJECTIVE: The age at onset of bipolar disorder is associated with clinical features of the illness, including duration, severity, and pattern of comorbidity with other disorders. Age at onset is familial and heritable, and it correlates inversely with the prevalence of bipolar disorder among relatives. Because age at onset may have utility in resolving the complexity and heterogeneity of the disorder, the authors sought to identify chromosomal loci that harbor the genes influencing this trait. METHOD: A genome scan of 539 genotyped people in 97 families ascertained for the NIMH Bipolar Disorder Genetics Initiative was performed by using multipoint variance-components linkage analysis. RESULTS: The age at onset of mania was significantly heritable in these families. Three chromosomal regions yielded nonsignificant but suggestive multipoint lod scores greater than 2.5, with the strongest evidence observed at markers D12S1292, GATA31B, and GATA50C, on chromosomes 12p, 14q, and 15q, respectively. CONCLUSIONS: Although firm conclusions await an independent replication, these results suggest that three regions of the genome may contain genes influencing the age at onset of mania in bipolar disorder. To the authors' knowledge, these regions have not been implicated previously in risk for the disorder, suggesting that separate sets of genes influence disease susceptibility and the age at which it appears." [Abstract]