Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P
Molecular genetics of attention-deficit/hyperactivity disorder.
Biol Psychiatry. 2005 Jun 1;57(11):1313-23.
Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25. [Abstract]

Kustanovich V, Merriman B, McGough J, McCracken JT, Smalley SL, Nelson SF.
Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder.
Mol Psychiatry 2003 Mar;8(3):309-15
"Attention-deficit hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder, affecting 5-10% of school-age children. Although the biological basis of this disorder is unknown, twin and family studies provide strong evidence that ADHD has a genetic basis involving multiple genes. A previous study found an association between ADHD and two polymorphisms in the 3' untranslated region (UTR) of SNAP-25, a gene encoding a synaptic vesicle docking protein known to play a role in the hyperactivity observed in the Coloboma mouse strain. In this paper, we test biased transmission of the 3' UTR SNAP-25 haplotype using a larger ADHD sample of 113 families with 207 affected children. Using the transmission disequilibrium test (TDT), we found a trend consistent with biased transmission of the TC haplotype of SNAP-25 in all transmissions and detected a significant distortion (P=0.027) when paternal transmissions were evaluated." [Abstract]

Mill J, Richards S, Knight J, Curran S, Taylor E, Asherson P
Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD.
Mol Psychiatry. 2004 Aug;9(8):801-10.
Several lines of evidence suggest a role for SNAP-25 (synaptosomal-associated protein of 25 kDa) in the genetic aetiology of ADHD. Most notable is the coloboma mouse mutant, which displays spontaneous hyperactivity and is hemizygous for a deletion spanning this gene. We have screened the SNAP-25 gene using denaturing high-performance liquid chromatography and sequencing, and genotyped six polymorphic single-nucleotide polymorphisms and two microsatellites in a clinically ascertained sample of 188 probands. Several markers were found to show association with ADHD, both individually and in combination with other markers to form multimarker haplotypes. Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting. Overall our data provide some evidence for a role of this gene in ADHD, although the precise causal functional variant is yet to be ascertained. [Abstract]

Brophy K, Hawi Z, Kirley A, Fitzgerald M, Gill M.
Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population.
Mol Psychiatry 2002;7(8):913-7
"Several lines of evidence have suggested that ADHD is a polygenic disorder produced by the interaction of several genes each of a minor effect. Synaptosomal-associated protein 25 (SNAP-25) is a presynaptic plasma membrane protein which is expressed highly and specifically in the nerve cells. The gene encodes a protein essential for synaptic vesicle fusion and neurotransmitter release. Animal model studies showed that the coloboma mouse mutant has a hyperactive phenotype similar to that of ADHD. The hyperactive phenotype of this model has been shown to be the result of a deletion of the SNAP-25 gene. DNA variations within or closely mapped to the SNAP-25 gene may alter the level of expression and hence may have an effect on the function of synaptic vesicle fusion and neurotransmitter release. Using HHRR and TDT we analysed 93 ADHD nuclear families from Ireland and found increased preferential transmission of SNAP-25/DdeI allelel to ADHD cases; HHRR (chi(2) = 6.55, P = 0.01) and linkage (TDT) (chi(2) = 6.5, P = 0.015). In contrast to our findings, Barr et al(1) reported an increased transmission of allele 2 of the DdeI polymorphism though this was not statistically significant. However, they also reported a significantly increased transmission of a haplotype (made of allele 1 of MnlI and allele 2 of the DdeI) in their Canadian ADHD sample. It is not clear what the role of SNAP-25 in ADHD is until these findings are either confirmed or refuted in other ADHD samples." [Abstract]

Mill J, Richards S, Knight J, Curran S, Taylor E, Asherson P.
Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD.
Mol Psychiatry. 2004 Mar 9 [Epub ahead of print]
"Several lines of evidence suggest a role for SNAP-25 (synaptosomal-associated protein of 25 kDa) in the genetic aetiology of ADHD. Most notable is the coloboma mouse mutant, which displays spontaneous hyperactivity and is hemizygous for a deletion spanning this gene. We have screened the SNAP-25 gene using denaturing high-performance liquid chromatography and sequencing, and genotyped six polymorphic single-nucleotide polymorphisms and two microsatellites in a clinically ascertained sample of 188 probands. Several markers were found to show association with ADHD, both individually and in combination with other markers to form multimarker haplotypes. Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting. Overall our data provide some evidence for a role of this gene in ADHD, although the precise causal functional variant is yet to be ascertained." [Abstract]

Feng Y, Crosbie J, Wigg K, Pathare T, Ickowicz A, Schachar R, Tannock R, Roberts W, Malone M, Swanson J, Kennedy JL, Barr CL
The SNAP25 gene as a susceptibility gene contributing to attention-deficit hyperactivity disorder.
Mol Psychiatry. 2005 Aug 9;
The synaptosomal-associated protein of 25 kDa gene (SNAP25) has been suggested as a genetic susceptibility factor in attention-deficit hyperactivity disorder (ADHD) based on the mouse strain coloboma. This strain is hemizygous for the SNAP25 gene and displays hyperactivity that responds to dextroamphetamine, but not to methylphenidate. Previously, we reported association of SNAP25 and ADHD using two polymorphisms. To further investigate this gene, we screened the exons for DNA variation and genotyped ten additional polymorphisms in an expanded sample of families from Toronto and a second sample of families collected in Irvine, CA. Significant results were observed in the Toronto sample for four markers, although not in the Irvine sample. The paper discusses the possible influence of the selection criteria on these differential results. The Irvine sample selected subjects that met the DSM-IV combined subtype diagnosis, whereas the Toronto sample included all subtypes. Analysis of the DSM-IV subtypes in the Toronto sample indicated that the differential results were not attributable to ADHD subtype. Differences in ethnicity, differential medication response, and other clinical characteristics of the samples cannot be ruled out at this time. Quantitative analysis of the dimensions of hyperactivity/impulsivity and inattention in the Toronto sample found that both behavioral traits were associated with SNAP25. Our findings continue to support SNAP25 in the susceptibility to ADHD. [Abstract]

Brookes KJ, Knight J, Xu X, Asherson P
DNA pooling analysis of ADHD and genes regulating vesicle release of neurotransmitters.
Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4;
ADHD is one of the most prevalent, and heritable behavioural disorders in childhood. Genetic associations have been reported with polymorphic variants within or near to dopamine pathway genes. Recently snap-25 has also shown association with ADHD in several datasets. We therefore investigated other genes that produce proteins that interact with SNAP-25 in the mechanism of vesicular release of neurotransmitters at the synapse. A total of 106 SNPs were screened for minor allele frequency greater than 5% and 61 SNPs selected for analysis in DNA pools made up from an ADHD clinical sample of DSM-IV combined type probands (n = 180) and a control sample of 90 males and 90 females. Initial screening identified several SNPs that showed allele frequency differences of 5% or more. One SNP in the synaptophysin gene showed suggestive evidence of association following case-control and TDT analysis and warrants further investigation. [Abstract]

Turic D, Langley K, Mills S, Stephens M, Lawson D, Govan C, Williams N, Van Den Bree M, Craddock N, Kent L, Owen M, O'Donovan M, Thapar A.
Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD.
Mol Psychiatry. 2004 Feb;9(2):169-73.
"Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder, for which there is good evidence that genetic factors contribute to the aetiology. Recently reported linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P=5 x 10(-6)). The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, we undertook family-based association analysis in a sample of 238 families. We found significant evidence of association with a GRIN2A exon 5 polymorphism (chi(2)=5.7, P=0.01). Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted." [Abstract]

Adams J, Crosbie J, Wigg K, Ickowicz A, Pathare T, Roberts W, Malone M, Schachar R, Tannock R, Kennedy JL, Barr CL.
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region.
Mol Psychiatry. 2004 May;9(5):494-9.
"The glutamate system may be involved in the development of attention-deficit/hyperactivity disorder (ADHD) based on animal models and the role of N-methyl-D-aspartate receptors (NMDAR) in cognition and motor processes. A follow-up study of the first genome scan for ADHD identified significant evidence for linkage to the 16p13 region. The glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the NMDA receptor, resides in this region and a recent study has reported an association between this gene and ADHD. We tested for linkage between the alleles and haplotypes of four polymorphisms at the GRIN2A locus and ADHD in our sample of 183 nuclear families with 229 affected children. In contrast to previous findings, we did not identify any evidence for a relationship of these markers and ADHD. Owing to the role of GRIN2A in aspects of cognition, we investigated the relationship of this gene to the cognitive phenotypes of inhibitory control, verbal short-term memory and verbal working memory. There was no significant evidence of linkage between GRIN2A and these phenotypes. While the results were not significant in our sample, the previous association finding suggests that further study of this gene is warranted." [Abstract]

Turic D, Langley K, Williams H, Norton N, Williams NM, Moskvina V, Van den Bree MB, Owen MJ, Thapar A, O'Donovan MC
A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder.
Biol Psychiatry. 2005 Jun 1;57(11):1461-6.
BACKGROUND: The glutamatergic system, the major excitatory neurotransmitter system in the central nervous system (CNS) has been proposed as contributing a possible role in the etiology of attention deficit hyperactivity disorder (ADHD). This is based upon observations from animal, neuroimaging, neuroanatomical and neuropsychological studies. Genes related to glutamate function are therefore good functional candidates for this disorder. The SLC1A3 (Solute Carrier Family 1, member 3) gene encodes a glial glutamate transporter which maps to chromosome 5p12, a region of linkage that coincides in two published ADHD genome scans so far. SLC1A3 is thus both a functional and positional candidate gene for ADHD. METHODS: We have undertaken detailed association analysis of SLC1A3 using a multi-stage approach for candidate gene analysis. RESULTS: In a family-based sample (n = 299) we found a significant association between marker rs2269272 (p = .007) and ADHD. Two, two-marker haplotypes, rs2269272/rs3776581 (p = .016) and rs2269272/rs2032893 (p = .013) also yielded evidence of association. CONCLUSIONS: The results of our study suggest that genetic variation in SLC1A3 may contribute to susceptibility to ADHD. [Abstract]

Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N, Raybould R, Langley K, Bray N, Fitzgerald M, Owen MJ, O'donovan MC, Gill M, Thapar A, Craddock N
Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD.
Mol Psychiatry. 2005 May 31;
Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR=1.6, P=0.02) with a strong paternal effect (paternal transmissions: OR=3.2, P=0.0005; maternal transmissions: OR=1.00; P=1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved. [Abstract]

Friedel S, Horro FF, Wermter AK, Geller F, Dempfle A, Reichwald K, Smidt J, Brönner G, Konrad K, Herpertz-Dahlmann B, Warnke A, Hemminger U, Linder M, Kiefl H, Goldschmidt HP, Siegfried W, Remschmidt H, Hinney A, Hebebrand J
Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):96-9.
Several lines of evidence indicate an involvement of brain derived neurotrophic factor (BDNF) in body weight regulation and activity: heterozygous Bdnf knockout mice (Bdnf(+/-)) are hyperphagic, obese, and hyperactive; furthermore, central infusion of BDNF leads to severe, dose-dependent appetite suppression and weight loss in rats. We searched for the role of BDNF variants in obesity, eating disorders, and attention-deficit/hyperactivity disorder (ADHD). A mutation screen (SSCP and DHPLC) of the translated region of BDNF in 183 extremely obese children and adolescents and 187 underweight students was performed. Additionally, we genotyped two common polymorphisms (rs6265: p.V66M; c.-46C > T) in 118 patients with anorexia nervosa, 80 patients with bulimia nervosa, 88 patients with ADHD, and 96 normal weight controls. Three rare variants (c.5C > T: p.T2I; c.273G > A; c.*137A > G) and the known polymorphism (p.V66M) were identified. A role of the I2 allele in the etiology of obesity cannot be excluded. We found no association between p.V66M or the additionally genotyped variant c.-46C > T and obesity, ADHD or eating disorders. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html. [Abstract]

Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z
Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD.
Mol Psychiatry. 2005 Jun 7;
Genetic and pharmacological studies have emphasised the role of serotonin 5-hydroxytryptamine (5-HT) as a possible etiologic factor in the development of attention-deficit hyperactivity disorder (ADHD). Tryptophan hydroxylase (TPH) is a rate-limiting enzyme in the biosynthesis of serotonin from tryptophan. Originally, the TPH gene was thought to be widely expressed, but a second form of TPH, TPH2, was recently identified and the TPH2 gene was found to be solely expressed in the brain. We examined eight single nucleotide polymorphisms (SNP) in the TPH2 gene for association with ADHD in 179 Irish nuclear families. Transmission disequilibrium test analysis revealed significant association between the T allele of marker rs1843809 with the disorder (chi(2)=12.2, P=0.0006, OR=2.36). Stratifying data by the sex of the transmitting parent showed that this association was enhanced when paternal transmission was considered (OR=3.7). In addition, several haplotypes (all including the associated marker) were associated with ADHD. These preliminary findings suggest that TPH2 is a susceptibility locus for ADHD. Further confirmation, preferably from different ethnic groups, is required to firmly implicate TPH2 in the pathophysiology of ADHD.Molecular Psychiatry advance online publication, 7 June 2005; doi:10.1038/sj.mp.4001698. [Abstract]

Li J, Wang YF, Zhou RL, Yang L, Zhang HB, Wang B.
[Association between tryptophan hydroxylase gene polymorphisms and attention deficit hyperactivity disorder with or without learning disorder]
Zhonghua Yi Xue Za Zhi. 2003 Dec 25;83(24):2114-8.
"OBJECTIVE: To investigate the relationship between two tryptophan hydroxylasec (TPH) gene polymorphisms, A218C and A-6526G polymorphisms, and attention deficit hyperactivity disorder (ADHD) with or without learning disorder (LD). METHODS: Blood samples were taken from 132 trios with probands of ADHD with LD and 221 trios with probands of ADHD without LD. DNA was extracted and PCR was performed to amplify the fragments of A218C amd A-6526G polymorphisms. NheI and MboI were used to detect different alleles of the two polymorphisms separately. transmission disequilibriumtest (TDT) and haplotype analysis were used to test the association of the two polymorphisms of TPH gene and ADHD with or without LD. RESULTS: Haplotype block composed by A218C and A-6526G polymorphisms was related to ADHD with LD (chi(2) = 9.362, df = 3, P = 0.025). The haplotype of 218A/-6526G was significantly untransmitted to the probands with ADHD with LD (chi(2) = 9.252, df = 1, P = 0.002). CONCLUSION: TPH gene and the haplotype of 218A/-6526G may be related to ADHD with LD."
[Abstract]

Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R, Basile VS, Beitchman J, Kennedy JL.
The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder.
Mol Psychiatry 2003;8(1):98-102
"Recent research has suggested that serotonin, in addition to dopamine, may be involved in the development of attention deficit hyperactivity disorder (ADHD). Serotonin regulates dopaminergic neurotransmission in some areas of the brain via several 5-HT receptors including 5-HT1B. Animal studies have suggested the involvement of the 5-HT1B receptors in locomotor behaviour. For these reasons, we hypothesized that the 5-HT1B receptor gene may be a good candidate for genetic studies of ADHD. We tested for linkage disequilibrium between the 5-HT1B G861C polymorphism and ADHD in 115 families using the transmission disequilibrium test (TDT). We found evidence for a trend towards excess transmission of the 861G allele (chi(2)=2.91, P=0.09) that when further analysed for parental allele transmissions exhibited significantly greater paternal transmission of the G allele (chi(2)=4.80, P=0.03) to the affected child. Although preliminary, results from this study provide additional evidence that serotonin genes may be important risk factors for the development of ADHD." [Abstract]

Hawi Z, Dring M, Kirley A, Foley D, Kent L, Craddock N, Asherson P, Curran S, Gould A, Richards S, Lawson D, Pay H, Turic D, Langley K, Owen M, O'Donovan M, Thapar A, Fitzgerald M, Gill M.
Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample.
Mol Psychiatry 2002;7(7):718-25
"Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR(1B) and HTR(2A) (which encode the serotonin receptors 5-HT(1B) and 5-HT(2A) respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR(1B) in the total sample (for HHRR; chi(2) = 7.4, P = 0.0065 and TDT; (chi(2) = 6.4, P = 0.014). Analysis of HTR(2A) failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (chi(2) = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings." [Abstract]

Li J, Wang Y, Zhou R, Zhang H, Yang L, Wang B, Khan S, Faraone SV
Serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder in Chinese Han subjects.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):59-63.
Serotonin is an endogenous neurotransmitter that regulates aggressive and impulsive behavior and may be involved in the development of attention deficit hyperactivity disorder (ADHD). 5-HT1B knockout mice display hyperactivity, increased exploratory activity and aggression, reduced anxiety, increased vulnerability to cocaine self-administration, and elevated alcohol consumption. Many of these same behaviors are seen in patients with ADHD. Prior studies reported excess transmission of the 861G allele of 5-HT1B to ADHD offspring. We used the transmission disequilibrium test (TDT) and haplotype analysis to investigate the A-161T and G861C polymorphisms in the 5-HT1B receptor gene in ADHD trios from the Chinese Han population. We found no association with ADHD but did find a tendency for excess transmission of the 861G allele (chi(2) = 3.766, P = 0.052) and the G/A haplotype (chi(2) = 2.925, df = 1, P = 0.087), and under-transmission of C/A haplotype (chi(2) = 3.707, df = 1, P = 0.054) to offspring with inattentive ADHD. [Abstract]

Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R, Basile VS, Beitchman J, Kennedy JL.
Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD).
Mol Psychiatry 2000 Sep;5(5):537-41
"A recent study demonstrated that treatment of hyperactive mice with psychostimulants and serotonergic agents produced a calming effect that was dependent on serotonergic neurotransmission and was not associated with any changes in extracellular dopamine levels. The complex interaction between the serotonergic and dopaminergic neurotransmitter systems suggests that a balance between the two systems may be necessary for mediating hyperactive behaviour. Defects in serotonin system genes, therefore, may disrupt normal brain serotonin function causing an imbalance between these neurotransmitter systems leading to the development of attention deficit hyperactivity disorder (ADHD). Using the transmission disequilibrium test (TDT), the current study assesses for linkage disequilibrium between polymorphisms in the serotonin HTR2A receptor gene and ADHD. One hundred and fifteen families with a total of 143 children diagnosed with ADHD (DSM-IV) were genotyped for the His452 Tyr and the T102C polymorphisms in the serotonin HTR2A receptor gene. TDT analysis revealed a preferential transmission of the 452Tyr allele to the affected offspring (P = 0.03), suggesting linkage disequilibrium of this polymorphism with ADHD. This may open a new door in ADHD molecular genetics research, expanding the existing view of a catecholaminergic hypothesis to include a serotonergic hypothesis and should help elucidate the complex interplay among the neurotransmitter systems in the etiology of ADHD." [Abstract]

Li J, Wang Y, Qian Q, Wang B, Zhou R.
[Association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder in children]
Zhonghua Yi Xue Za Zhi 2002 Sep 10;82(17):1173-6
"OBJECTIVE: To stude the association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder (ADHD) in children. METHODS: Blood samples were taken from 323 6 approximately 17.5-year-old children with ADHD disgnosed based on the DSM-IV criteria, 182 healthy 18 approximately 49-year-old controls, and 195 pairs of parents of affected children, all of Han nationality. DNA was extracted. PCR was performed to examine the 5-hydroxytryptamine (5-HT)(2A) receptor T102C polymorphism. Transmission disequilibrium test (TDT) was used to test the association of alleles of 5-HT(2A) T102C polymorphic sites and AFDHD. RESULTS: The frequency of T102T in patients with ADHD combined subtype was lower than that in the controls (22.35 vs 33.5%, OR = 0.569, P = 0.028, 95% CI 0.344 - 0.943), and the frequency of T102C in patients with ADHD combined subtype was higher than that in the controls (64.0% vs 47.3%, OR = 1.987, P = 0.003, 95% CI 1.264 approximately 3.124). TDT showed biased transmission of the alleles of T102C polymorphism among families of girl patients with ADHD combined subtype (P = 0.031). CONCLUSION: For the ADHD combined subtype, the T102T genotype is a protective factor and the T102C genotype is a risk factor. For the girl with ADHD combined subtype, the allele C102 is a disease-predisposing gene." [Abstract]

Levitan RD, Masellis M, Basile VS, Lam RW, Jain U, Kaplan AS, Kennedy SH, Siegel G, Walker ML, Vaccarino FJ, Kennedy JL.
Polymorphism of the serotonin-2A receptor gene (HTR2A) associated with childhood attention deficit hyperactivity disorder (ADHD) in adult women with seasonal affective disorder.
J Affect Disord 2002 Sep;71(1-3):229-33
"INTRODUCTION: Several lines of research point to a possible overlap between seasonal affective disorder (SAD) and attention deficit hyperactivity disorder (ADHD), particularly in females. There is also emerging evidence that variation of the 5-HT2A receptor gene (HTR2A) contributes to both SAD and ADHD. The current study investigated whether variation in HTR2A was associated with symptoms of childhood ADHD in adult women with SAD. METHOD: Sixty-six women with SAD were administered the Wender-Utah Rating Scale (WURS), which retrospectively assesses childhood ADHD, as part of an ongoing genetic study of SAD. WURS scores were compared across the three genotypic groups defined by the T102C polymorphism of HT2RA. RESULTS: Analysis of variance indicated a significant difference in mean 25-item WURS scores across the three genotypic groups (p = 0.035). Post-hoc tests revealed that the C/C genotypic group had a significantly higher mean score than both the T/T group and T/C group. Based on previously established WURS criteria, 38% of subjects with the C/C genotype, and none with the T/T genotype, had scores consistent with childhood ADHD. LIMITATIONS: The current sample size is small, and childhood ADHD diagnoses were based on retrospective recall. CONCLUSION: These preliminary results suggest a possible association between variation in HTR2A, childhood ADHD, and the later development of SAD in women." [Abstract]

Zoroglu SS, Erdal ME, Erdal N, Ozen S, Alasehirli B, Sivasli E.
No evidence for an association between the T102C and 1438 G/A polymorphisms of the serotonin 2A receptor gene in attention deficit/hyperactivity disorder in a Turkish population.
Neuropsychobiology 2003;47(1):17-20
"Disturbances in the serotonergic neurotransmission system have been implicated in the etiology of attention deficit/hyperactivity disorder (ADHD). As the importance of genetic factors is well established, genes encoding for proteins of the serotonergic pathway are important candidates to unravel the underlying genetic contribution. We previously demonstrated that the polymorphisms of the serotonin transporter gene promoter and regions of variable number of tandem repeats were involved in the pathogenesis of ADHD. The purpose of this study was to examine the relationship between ADHD and two polymorphisms (T102C and 1438 G/A) in the 5-HT2A gene in a sample of Turkish children. Using the PCR technique, these polymorphisms were assessed in 70 patients with ADHD and in 100 healthy controls. There was no significant difference between the frequencies of the T, C, G and A alleles of both groups. No association was found between the studied polymorphisms of the 5-HT2A gene and ADHD in this sample consisting of Turkish children. Overall, our results suggest that the investigated 5-HT2A polymorphisms are not major susceptibility factors in the etiology of ADHD." [Abstract]

Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL, Newbury DF, Crawford LR, Palmer CG, Woodward JA, Del'Homme M, Cantwell DP, Nelson SF, Monaco AP, Smalley SL.
A genomewide scan for loci involved in attention-deficit/hyperactivity disorder.
Am J Hum Genet 2002 May;70(5):1183-96
"Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs." [Abstract] [Full Text]

Ogdie MN, Macphie IL, Minassian SL, Yang M, Fisher SE, Francks C, Cantor RM, McCracken JT, McGough JJ, Nelson SF, Monaco AP, Smalley SL.
A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11.
Am J Hum Genet 2003 May;72(5):1268-79
"Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is a common, highly heritable neurobehavioral disorder of childhood onset, characterized by hyperactivity, impulsivity, and/or inattention. As part of an ongoing study of the genetic etiology of ADHD, we have performed a genomewide linkage scan in 204 nuclear families comprising 853 individuals and 270 affected sibling pairs (ASPs). Previously, we reported genomewide linkage analysis of a "first wave" of these families composed of 126 ASPs. A follow-up investigation of one region on 16p yielded significant linkage in an extended sample. The current study extends the original sample of 126 ASPs to 270 ASPs and provides linkage analyses of the entire sample, using polymorphic microsatellite markers that define an approximately 10-cM map across the genome. Maximum LOD score (MLS) analysis identified suggestive linkage for 17p11 (MLS=2.98) and four nominal regions with MLS values >1.0, including 5p13, 6q14, 11q25, and 20q13. These data, taken together with the fine mapping on 16p13, suggest two regions as highly likely to harbor risk genes for ADHD: 16p13 and 17p11. Interestingly, both regions, as well as 5p13, have been highlighted in genomewide scans for autism." [Abstract] [Full Text]

Ogdie MN, Fisher SE, Yang M, Ishii J, Francks C, Loo SK, Cantor RM, McCracken JT, McGough JJ, Smalley SL, Nelson SF
Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11.
Am J Hum Genet. 2004 Oct;75(4):661-8.
We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions--5p13, 6q12, 16p13, and 17p11--are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size. [Abstract]

Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ, McCracken JT, MacPhie IL, Francks C, Fisher SE, Cantor RM, Monaco AP, Nelson SF.
Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism.
Am J Hum Genet 2002 Oct;71(4):959-63
"Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a genetic etiology of the disorder, although putative alleles, principally in dopamine-related pathways suggested by candidate-gene studies, have very small effect sizes. We use affected-sib-pair analysis in 203 families to localize the first major susceptibility locus for ADHD to a 12-cM region on chromosome 16p13 (maximum LOD score 4.2; P=.000005), building upon an earlier genomewide scan of this disorder. The region overlaps that highlighted in three genome scans for autism, a disorder in which inattention and hyperactivity are common, and physically maps to a 7-Mb region on 16p13. These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism." [Abstract] [Full Text]

Jiang S, Xin R, Qian Y, Lin S, Li F, Wu X, Wang D, Tang G, Jiang K.
[Study of susceptibility loci located within Xp11 in attention deficit hyperactivity disorder]
Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2001 Jun;18(3):169-72
"OBJECTIVE: To detect the genetic relationship between monoamine oxidase(MAO) A type gene and attention deficit hyperactivity disorder(ADHD) in Chinese. METHODS: The haplotype-based haplotype relative risk(HHRR) and the transmission disequilibrium test(TDT) methods were used to analyze the genetic association and linkage in 60 ADHD children and their parents. RESULTS: In this sample were found significant association (chi(2)=4.90, P<0.05) and linkage (chi(2)=4.84, P<0.05) between the MAOCA 114bp allele and DSM-III-R-diagnosed ADHD in trios composed of father, mother and affected offspring. CONCLUSION: The above results suggested that ADHD was associated and in linkage with MAO A gene, and the susceptibility loci might reside in chromosome Xp11 for ADHD." [Abstract]

Willcutt EG, Pennington BF, Smith SD, Cardon LR, Gayan J, Knopik VS, Olson RK, DeFries JC.
Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder.
Am J Med Genet 2002 Apr 8;114(3):260-8
"Comorbidity is pervasive among both adult and child psychiatric disorders; however, the etiological mechanisms underlying the majority of comorbidities are unknown. This study used genetic linkage analysis to assess the etiology of comorbidity between reading disability (RD) and attention-deficit hyperactivity disorder (ADHD), two common childhood disorders that frequently co-occur. Sibling pairs (N = 85) were ascertained initially because at least one individual in each pair exhibited a history of reading difficulties. Univariate linkage analyses in sibling pairs selected for ADHD from within this RD-ascertained sample suggested that a quantitative trait locus (QTL) on chromosome 6p is a susceptibility locus for ADHD. Because this QTL is in the same region as a well-replicated QTL for reading disability, subsequent bivariate analyses were conducted to test if this QTL contributed to comorbidity between the two disorders. Analyses of data from sib pairs selected for reading deficits revealed suggestive bivariate linkage for ADHD and three measures of reading difficulty, indicating that comorbidity between RD and ADHD may be due at least in part to pleiotropic effects of a QTL on chromosome 6p." [Abstract]

Jiang S, Xin R, Wu X, Lin S, Qian Y, Ren D, Tang G, Wang D.
Association between attention deficit hyperactivity disorder and the DXS7 locus.
Am J Med Genet 2000 Jun 12;96(3):289-92
"Attention deficit hyperactivity disorder (ADHD) is a prevalent disorder in children. The etiology of this disease is not clear. Genetics studies have suggested the involvement of the dopamine DRD-4 receptor gene and dopamine transporter gene (DAT1). Clinical studies have shown that monoamine oxidase-B (MAO-B) inhibitors are effective in the treatment of ADHD. These findings suggest that monoamine oxidase (MAO) genes might be involved in the origin of ADHD. In the present work, the DXS7 locus of chromosome X, which is closely linked to MAO genes, was selected as a marker to study the possible association between ADHD and MAO genes in the Chinese population. Haplotype-based haplotype relative risk (HHRR) and the transmission disequilibrium test (TDT) methods were employed to analyze the association and the linkage disequilibrium, respectively. Significant association (X(2) = 15.86; 1 df; P < 0.001) and linkage (X(2) = 14.88; 1 df; P < 0.001) were detected between the 157-bp allele of the DXS7 locus and the DSM-III-R-diagnosed ADHD (N = 72) in trios composed of father, mother, and affected offspring. The data suggested that ADHD was associated and in linkage with DXS7 locus." [Abstract]

Park L, Nigg JT, Waldman ID, Nummy KA, Huang-Pollock C, Rappley M, Friderici KH
Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD.
Mol Psychiatry. 2005 Jun;10(6):572-80.
Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A, showed inconsistent results with regard to an MspI polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define HhaI and DraI restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the MspI RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P=0.03), and the quantitative TDT showed association of this polymorphism with the inattentive (P=0.003) and hyperactive-impulsive (P=0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P=0.001) and hyperactive-impulsive (P=0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism. [Abstract]

Comings DE, Gade-Andavolu R, Gonzalez N, Blake H, Wu S, MacMurray JP.
Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects.
Clin Genet 1999 Mar;55(3):160-72
"Halperin et al. (Halperin JM. Newcorn JH, Koda VH, Pick L, McKay KE, Knott P. Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension. J Am Acad Child Adolesc Psychiatry 1997: 36: 1688 1696) reported a significant increase in plasma norepinephrine (NE) in attention-deficit hyperactivity disorder (ADHD) children with reading and other cognitive disabilities compared to ADHD children without learning disabilities (LD). We examined the hypothesis that ADHD + LD was associated with NE dysfunction at a molecular genetic level by testing for associations and additive effects between polymorphisms at three noradrenergic genes the adrenergic alpha2A receptor (ADRA2A), adrenergic alpha2C receptor (ADRA2C), and dopamine beta-hydroxylase (DBH) genes. A total of 336 subjects consisting of 274 individuals with Tourette syndrome (TS) and 62 normal controls were genotyped. Regression analysis showed a significant correlation between scores for ADHD, a history of LD, and poor grade-school academic performance that was greatest for the additive effect of all three genes. Combined, these three genes accounted for 3.5% of the variance of the ADHD score (p = 0.0005). There was a significant increase in the number of variant NE genes progressing from subjects without ADHD (A-) or learning disorders (LD-) to A + LD - to A - LD + to A + LD + (p = 0.0017), but no comparable effect for dopamine genes. These data support an association between NE genes and ADHD, especially in ADHD + LD subjects." [Abstract]

Comings DE, Gonzalez NS, Li S-C C, MacMurray J.
A "line item" approach to the identification of genes involved in polygenic behavioral disorders: The Adrenergic alpha2A (ADRA2A) gene.
Am J Med Genet 2003 Apr 1;118B(1):110-4
"The usual approach for using single base pair polymorphisms (SNPs) for the investigation of the genetics of behavioral disorders is to examine a single diagnostic syndrome or personality trait based on variables relating to a cluster of behavioral symptoms. However, since some of these variables may address behaviors that are associated with one allele while others are associated with the other allele, the overall association may be non-significant and significant sub-syndromal associations may be missed. Thus, we have reversed the process in a technique we term a "line item" approach. As a test of the technique we have examined the association between genotypes of a C- > G-1291 Msp I promotor SNP of the ADRA2A gene and 390 individual symptoms from a structured review of DSM-IV criteria for twelve different groups of symptoms. We examined 334 individuals consisting of controls and subjects with Tourette syndrome (TS). Based on the mean scores for each genotype, those symptoms that were individually significant at alpha </= 0.05 fell into three major groups by mode of inheritance: allele 1 codominant (11 > 12 > 22), allele 2 codominant (22 > 12 > 11), and negative heterosis (12 < 11, 22). Within each mode of inheritance group, the number of symptoms that were significant for the twelve symptom clusters was compared by chi-square analysis. This showed that symptoms were drawn from the diagnostic groups in a significantly non-random fashion. Thus, the allele 1 codominant symptoms came from the anxiety, affective, schizoid, and somatization diagnostic groups (internalizing symptoms) (chi(2) = 80.0, d.f. = 11, P </= 0.0000001), while the allele 2 codominant symptoms came from the ADHD and oppositional defiant/conduct disorder diagnostic groups (externalizing symptoms) (chi(2) = 81.0, d.f. = 11, P </= 0.0000001). The questions that fell in the negative heterosis type of inheritance were not significantly associated with specific diagnostic groups (P = 0.87). These results showed that the ADRA2A gene was associated with symptoms of autonomic, sympathetic dysfunction from different diagnostic groups. The advantages of the "line item" approach include (a) the identification of the symptoms associated with each allele, (b) the identification of symptom clusters independent of DSM diagnoses, (c) the elucidation of heterosis and other mode of inheritance effects, (d) the distinction between an association with a primary disorder versus a comorbid disorder, (e) the identification of associations with sub-syndromal symptom clusters that do meet full DSM-IV criteria, and (f) the identification of symptom clusters across databases." [Abstract]

Roman T, Schmitz M, Polanczyk GV, Eizirik M, Rohde LA, Hutz MH.
Is the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention-deficit/hyperactivity disorder?
Am J Med Genet. 2003 Jul 1;120B(1):116-20.
"Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex childhood-onset psychiatric disorder characterized by marked symptoms of inattention, hyperactivity, and impulsivity. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Although most of the molecular studies have investigated the dopamine D4 receptor gene (DRD4) and the dopamine transporter gene (DAT1) genes in its etiology, pharmacological and brain imaging evidences seem to indicate that genes of the adrenergic system could also be attractive for association studies. We investigated a sample of 96 Brazilian ADHD children and adolescents and their parents for the ADRA2A MspI polymorphism. Although no association with either MspI allele was observed through the haplotype relative risk (HRR) analysis, effects of the ADRA2A gene on inattention and combined (inattention + hyperactivity/impulsivity) symptom scores were detected (U = 222.5, z = 2.19, P = 0.03; and U = 208.5, z = 2.32, P = 0.02, respectively). Our results suggest that the ADRA2A gene might have a small effect on ADHD susceptibility or that this gene might modulate the severity of the disorder. They are also consistent with the noradrenergic theories of ADHD, suggesting a role for the alpha2A adrenergic receptors in the disorder." [Abstract]

Comings DE, Gade-Andavolu R, Gonzalez N, Wu S, Muhleman D, Blake H, Dietz G, Saucier G, MacMurray JP.
Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: multivariate regression analysis of 20 genes.
Clin Genet 2000 Mar;57(3):178-96
"The present study is based on the proposal that complex disorders resulting from the effects of multiple genes are best investigated by simultaneously examining multiple candidate genes in the same group of subjects. We have examined the effect of 20 genes for dopamine, serotonin, and noradrenergic metabolism on a quantitative score for attention deficit hyperactivity disorder (ADHD) in 336 unrelated Caucasian subjects. The genotypes of each gene were assigned a score from 0 to 2, based on results from the literature or studies in an independent set of subjects (literature-based scoring), or results based on analysis of variance for the sample (optimized gene scoring). Multivariate linear regression analysis with backward elimination was used to determine which genes contributed most to the phenotype for both coding methods. For optimized gene scoring, three dopamine genes contributed to 2.3% of the variance, p = 0.052; three serotonin genes contributed to 3%, p = 0.015; and six adrenergic genes contributed to 6.9%, p = 0.0006. For all genes combined, 12 genes contributed to 11.6% of the variance, p = 0.0001. These results indicate that the adrenergic genes play a greater role in ADHD than either the dopaminergic or serotonergic genes combined. The results using literature-based gene scoring were similar. An examination of two additional comorbid phenotypes, conduct disorder and oppositional defiant disorder (ODD), indicated they shared genes with ADHD. For ODD different genotypes of the same genes were often used. These results support the value of the simultaneous examination of multiple candidate genes." [Abstract]

Kent L, Doerry U, Hardy E, Parmar R, Gingell K, Hawi Z, Kirley A, Lowe N, Fitzgerald M, Gill M, Craddock N.
Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis.
Mol Psychiatry 2002;7(8):908-12
"Reduced central serotonergic activity has been implicated in poor impulse regulation and aggressive behaviour in animals, adults and also young children.(1,2) Two recently published studies have implicated variation at a polymorphism in the promoter of the serotonin transporter (5HTT; hSERT) in influencing susceptibility to ADHD.(3,4) Consistent with these results we have also found a trend for the long allele of the promoter polymorphism to influence susceptibility to ADHD in a sample of 113 ADHD parent proband trios (65 transmissions vs 49 non-transmissions, chi(2) = 2.25, P = 0.13). A pooled analysis of our, and these published results demonstrated a significant over representation of the long allele of the promoter in ADHD probands compared to controls (chi(2) = 7.14, P = 0.008). We have also examined two other 5HTT polymorphisms (the VNTR in intron 2 and the 3' UTR SNP). TDT analysis demonstrated preferential transmission of the T allele of the 3' UTR SNP (chi(2) = 4.06, P = 0.04). In addition, ETDT analysis of haplotypes demonstrated significant preferential transmission of haplotypes containing the T allele of the 3' UTR SNP with the long allele of the promoter polymorphism (chi(2) = 13.18, 3 df, P = 0.004) and the 10 repeat of the VNTR (chi(2) = 8.77, 3 df, P = 0.03). This study provides further evidence for the possible involvement of the serotonin transporter in susceptibility to ADHD." [Abstract]

Langley K, Payton A, Hamshere ML, Pay HM, Lawson DC, Turic D, Ollier W, Worthington J, Owen MJ, O'Donovan MC, Thapar A.
No evidence of association of two 5HT transporter gene polymorphisms and attention deficit hyperactivity disorder.
Psychiatr Genet. 2003 Jun;13(2):107-10.
"OBJECTIVES: Three studies to date have found evidence (or a trend for evidence) of linkage and association between the long allele of the 44 base pair repeat insertion/deletion 5-HTT functional polymorphism (5-HTTLPR) and attention deficit hyperactivity disorder (ADHD). In an attempt to replicate these findings, we examined this polymorphism and a variable number tandem repeat in the second intron of 5-HTT for association with ADHD. METHODS: One hundred and fifty children who met diagnostic criteria for ADHD and their parents (where available) were genotyped for these polymorphisms. Analysis was undertaken using the transmission disequilibrium test and haplotype analysis, as well as case-control comparisons using a control group of 121 individuals. RESULTS: No association between either the 5-HTTLPR or the variable number tandem repeat (VNTR) in ADHD was found (extended transmission disequilibrium test; P=0.37 and P=0.62, respectively). Haplotype analysis was also non-significant. Further analysis revealed no evidence of association in the subgroups of those without conduct disorder and in medication non-responders. CONCLUSIONS: Failure to replicate findings from previous studies may be due to a lack of statistical power. However, given recent findings by Kent et al. (2002) of association with another polymorphism in the 5HTT gene, we hypothesise that previous positive findings may have arisen by the LPR and VNTR being in linkage disequilibrium with the true susceptibility polymorphism." [Abstract]

Zoroglu SS, Erdal ME, Alasehirli B, Erdal N, Sivasli E, Tutkun H, Savas HA, Herken H.
Significance of serotonin transporter gene 5-HTTLPR and variable number of tandem repeat polymorphism in attention deficit hyperactivity disorder.
Neuropsychobiology 2002;45(4):176-81
"The purpose of this study was to evaluate the relationship between attention deficit hyperactivity disorder (ADHD) and polymorphism of the two regions of the 5-HTT gene [variable number of tandem repeats (VNTR) and 5-HTTLRR] in a sample of Turkish children. Using the PCR technique, these polymorphisms were assessed in 71 patients with ADHD and 128 healthy controls. The 5-HTTLPR S/S genotype was significantly lower in the patients than in the controls (p = 0.018). Homozygous and heterozygous L variant predominated in the ADHD group. But the VNTR STin2.12/12 genotype was significantly less found in the patients than in the controls (p = 0.001). There was no significant difference between the frequency of the short (S), long, 10, and 12 alleles of both groups. The lack of an S/S variant of 5-HTTLPR polymorphism of the STin2.12/12 variant of VNTR polymorphism appears to be associated with an increased risk of ADHD." [Abstract]

Curran S, Purcell S, Craig I, Asherson P, Sham P
The serotonin transporter gene as a QTL for ADHD.
Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):42-7.
Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD. [Abstract]

Xu X, Mill J, Chen CK, Brookes K, Taylor E, Asherson P
Family-based association study of serotonin transporter gene polymorphisms in attention deficit hyperactivity disorder: No evidence for association in UK and Taiwanese samples.
Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4;
Five independent studies have reported associations between serotonin transporter gene (5-HTT) polymorphisms and attention deficit hyperactivity disorder (ADHD). Four studies found evidence for association between the long-allele of a 44-base pair insertion/deletion polymorphism (5-HTTLPR), one of the studies found association to a variable number tandem repeat within intron 2, another to the T-allele of a single base pair substitution in the 3'-untranslated regions and another reported preferential transmission of a haplotype of the three markers (long-allele/10-repeat-allele/T-allele). One further study found no evidence for these associations. We investigated the association of these three markers in two samples of ADHD patients from the United Kingdom (n = 197) and Taiwan (n = 212), using within-family tests of association. No association was found between any of the three markers in either of the two populations. Although we found some evidence for the preferential transmission of a rare haplotype (long-allele/9-repeat-allele/T-allele; chi(2) = 4.5, P = 0.034), we concluded that this most likely occurred by chance factors alone. [Abstract]

Kim SJ, Badner J, Cheon KA, Kim BN, Yoo HJ, Kim SJ, Cook E, Leventhal BL, Kim YS
Family-based association study of the serotonin transporter gene polymorphisms in Korean ADHD trios.
Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4;
The dopamine (DA) system has been implicated in attention deficit hyperactivity disorder (ADHD) based on pharmacologic evidence. Because of an interaction between the serotonin (5-HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene. Two common polymorphisms, 5-HTTLPR and the intron 2 VNTR, have been studied for association in ADHD, with both positive (increased frequency of long allele of 5-HTTLPR and decreased frequency of 12 repeats of the intron 2 VNTR) and negative findings. However, there has not been an association study in an East Asian ADHD population. In this study, we examined the genotypes of these two polymorphisms in 126 Korean ADHD families and investigated linkage disequilibrium (LD) between SLC6A4 and ADHD, using the transmission disequilibrium test (TDT) and haplotype analysis. Additionally, association with quantitative measures of inattention, hyperactivity-impulsivity, and overall severity was tested using logistic regression and QTDT analysis. TDT of both polymorphisms and haplotype analysis failed to detect LD. However, after excluding ADHD NOS subtype, TDT revealed nominally significant LD between 5-HTTLPR and ADHD (chi(2) = 4.9, P = 0.036). QTDT revealed positive association between 12 repeats of the intron 2 VNTR and attention (P = 0.031), but case-control and TDT logistic regression analyses were negative. These markers have low heterozygosity in the Korean population, which would be expected to reduce the power of association. This result suggests that future studies should include more polymorphic markers and subjects to thoroughly investigate a potential association between SLC6A4 and ADHD in the Korean population. (c) 2005 Wiley-Liss, Inc. [Abstract]

Comings DE, Chen C, Wu S, Muhleman D.
Association of the androgen receptor gene (AR) with ADHD and conduct disorder.
Neuroreport 1999 May 14;10(7):1589-92
"The male predominance of externalizing behaviors suggests that the X-linked androgen gene might be involved. Since the shorter alleles of the CAG and GGC polymorphisms of the AR gene are associated with increased gene expression we sought to determine whether they were also associated with externalizing behaviors. We examined 302 subjects consisting of Tourette syndrome probands and controls. ANOVA showed a significant association between the AR haplotypes and ADHD (p < 0.0001), conduct disorder (CD; p < 0.017), and oppositional defiant disorder (ODD; p < 0.004) with the lowest scores in those with the longer alleles at both polymorphisms. These results suggest that genetic variation at the human AR gene plays a role in human externalizing disorders." [Abstract]

Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C, Sprich-Buckminster S, Ugaglia K, Jellinek MS, Steingard R, et al.
Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples.
Arch Gen Psychiatry 1992 Sep;49(9):728-38
"We examined 140 probands with attention deficit hyperactivity disorder, 120 normal controls, and their 822 first-degree relatives using "blind" raters and structured diagnostic interviews. Compared with controls, probands with attention deficit hyperactivity disorder were more likely to have conduct, mood, and anxiety disorders. Compared with relatives of controls, relatives of probands with attention deficit hyperactivity disorder had a higher risk for attention deficit hyperactivity disorder, antisocial disorders, major depressive disorder, substance dependence, and anxiety disorders. Patterns of comorbidity indicate that attention deficit hyperactivity disorder and major depressive disorders may share common familial vulnerabilities, that attention deficit hyperactivity disorder plus conduct disorder may be a distinct subtype, and that attention deficit hyperactivity disorder and anxiety disorders are transmitted independently in families. These results extend previous findings indicating family-genetic influences in attention deficit hyperactivity disorder by using both pediatrically and psychiatrically referred proband samples. The distributions of comorbid illnesses in families provide further validation for subgrouping probands with attention deficit hyperactivity disorder by comorbidity." [Abstract]

Biederman J, Faraone SV, Keenan K, Knee D, Tsuang MT.
Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder.
J Am Acad Child Adolesc Psychiatry 1990 Jul;29(4):526-33
"Using family study methodology and assessments made by blind raters, this study evaluated family-genetic and psychosocial risk factors for DSM-III attention deficit disorder (ADD) among the 457 first-degree relatives of clinically referred children and adolescents with ADD (N = 73), compared with psychiatric (N = 26) and normal controls (N = 26). Relatives of ADD probands had a higher morbidity risk for ADD (25.1% versus 5.3% versus 4.6%, ps less than 0.00001), antisocial disorders (25.3% versus 6.9% versus 4.2%, ps less than 0.00001), and mood disorders (27.1% versus 13.9%, p = 0.038 and 27.1% versus 3.6%, p = 0.00001) than did relatives of psychiatric and normal controls. The increased risk for ADD could not be accounted for by gender or generation of relative, the age of proband, social class, or the intactness of the family. These results confirm and extend previous findings indicating important family-genetic risk factors in ADD." [Abstract]

Barr CL, Wigg KG, Feng Y, Zai G, Malone M, Roberts W, Schachar R, Tannock R, Kennedy JL.
Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor.
Mol Psychiatry 2000 Sep;5(5):548-51
"A recent study has suggested a possible association of a polymorphism near the dopamine D5 receptor gene (DRD5) and attention-deficit hyperactivity disorder. The polymorphism studied was a (CA)n repeat located in the cosmid containing the D5 receptor gene2 and the allele that was reported to be associated with attention-deficit hyperactivity disorder (ADHD) was the 148-bp allele. In this study we sought to replicate this finding by testing for biased transmission of the alleles at this same polymorphism in a sample of 92 families with an ADHD proband. We did not observe significant evidence for biased transmission of the 148-bp allele, however we did observe biased transmission of two other alleles, the 136-bp allele and the 146-bp allele. For these two alleles the bias was for these two alleles not to be transmitted to the ADHD children. The number of informative transmissions for these two alleles was small, therefore it would be premature to make any conclusions from our study concerning the role of DRD5 in ADHD." [Abstract]

Barr CL, Wigg K, Zai G, Roberts W, Malone M, Schachar R, Tannock R, Kennedy JL.
Attention-deficit hyperactivity disorder and the adrenergic receptors alpha 1C and alpha 2C.
Mol Psychiatry 2001 May;6(3):334-7
"The adrenergic system has been hypothesized to be involved in the etiology of attention-deficit hyperactivity disorder (ADHD) based on pharmacological interventions and animal models. Noradrenergic neurons are implicated in the modulation of vigilance, improvement of visual attention, initiation of adaptive response, learning and memory. In this study we tested the genes for two adrenergic receptors, alpha 1C (ADRA1C) located on chromosome 8p11.2, and alpha 2C (ADRA2C) located on chromosome 4p16, as genetic susceptibility factors in ADHD. For the adrenergic receptor alpha 1C we used a C to T polymorphism that results in a change of Cys to Arg at codon 492 for the linkage study. For the adrenergic receptor alpha 2C gene we examined a dinucleotide repeat polymorphism located approximately 6 kb from the gene. We examined these polymorphisms in a sample of 103 families ascertained through an ADHD proband. Using the transmission disequilibrium test, we did not observe biased transmission of any of the alleles of these polymorphisms. We conclude that the alleles at the polymorphisms tested in these two genes are not linked to the ADHD phenotype in this sample of families." [Full Text]

De Luca V, Muglia P, Vincent JB, Lanktree M, Jain U, Kennedy JL.
Adrenergic alpha 2C receptor genomic organization: association study in adult ADHD.
Am J Med Genet. 2004 May 15;127B(1):65-7.
"Attention deficit hyperactivity disorder (ADHD) is a chronic psychiatric condition in children and follow up studies have indicated that one to two thirds of patients continue to suffer from ADHD during late adolescence and adulthood. Pharmacological interventions, such as the new selective noradrenergic reuptake inhibitor, atomoxetine, suggest the adrenergic system as candidate in ADHD. We examined for the presence of linkage disequilibrium between the alpha 2C adrenergic receptor (ADRA2C) microsatellite polymorphism upstream of the ADRA2C gene and adult ADHD in a sample of nuclear families. We also present new information on the genomic organization of the ADRA2C locus. The microsatellite polymorphism was typed in 128 small families and analyzed using the Transmission Disequilibrium Test (TDT). There was no preferential transmission of any allele. These findings exclude a strong effect of this ADRA2C marker on risk for ADHD in our sample of adult proband families." [Abstract]

de Silva MG, Elliott K, Dahl HH, Fitzpatrick E, Wilcox S, Delatycki M, Williamson R, Efron D, Lynch M, Forrest S.
Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype.
J Med Genet. 2003 Oct;40(10):733-40.
"BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a complex condition with high heritability. However, both biochemical investigations and association and linkage studies have failed to define fully the underlying genetic factors associated with ADHD. We have identified a family co-segregating an early onset behavioural/developmental condition, with features of ADHD and intellectual disability, with a pericentric inversion of chromosome 3, 46N inv(3)(p14:q21). METHODS: We hypothesised that the inversion breakpoints affect a gene or genes that cause the observed phenotype. Large genomic clones (P1 derived/yeast/bacterial artificial chromosomes) were assembled into contigs across the two inversion breakpoints using molecular and bioinformatic technologies. Restriction fragments crossing the junctions were identified by Southern analysis and these fragments were amplified using inverse PCR. RESULTS: The amplification products were subsequently sequenced to reveal that the breakpoints lay within an intron of the dedicator of cytokinesis 3 (DOCK3) gene at the p arm breakpoint, and an intron of a novel member of the solute carrier family 9 (sodium/hydrogen exchanger) isoform 9 (SLC9A9) at the q arm. Both genes are expressed in the brain, but neither of the genes has previously been implicated in developmental or behavioural disorders. CONCLUSION: These two disrupted genes are candidates for involvement in the pathway leading to the neuropsychological condition in this family." [Abstract] [Full Text]

Bakker SC, Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls DL, Monsuur AJ, Slot Rv R, Minderaa RB, Gunning WB, Pearson PL, Sinke RJ.
A whole-genome scan in 164 dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q.
Am J Hum Genet 2003 May;72(5):1251-60
"A genome scan was performed on 164 Dutch affected sib pairs (ASPs) with attention-deficit/hyperactivity disorder (ADHD). All subjects were white and of Dutch descent and were phenotyped according to criteria set out in the Diagnostic and Statistical Manual Of Mental Disorders, 4th edition. Initially, a narrow phenotype was defined, in which all the sib pairs met the full ADHD criteria (117 ASPs). In a broad phenotype, additional sib pairs were included, in which one child had an autistic-spectrum disorder but also met the full ADHD criteria (164 ASPs). A set of 402 polymorphic microsatellite markers with an average intermarker distance of 10 cM was genotyped and analyzed using the Mapmaker/sibs program. Regions with multipoint maximum likelihood scores (MLSs) >1.5 in both phenotypes were fine mapped with additional markers. This genome scan indicated several regions of interest, two of which showed suggestive evidence for linkage. The most promising chromosome region was located at 15q, with an MLS of 3.54 under the broad phenotype definition. This region was previously implicated in reading disability and autism. In addition, MLSs of 3.04 and 2.05 were found for chromosome regions 7p and 9q in the narrow phenotype. Except for a region on chromosome 5, no overlap was found with regions mentioned in the only other independent genome scan in ADHD reported to date." [Abstract] [Full Text]

Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG, Rapoport JL, Berg K, Bailey-Wilson JE, Muenke M
Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11.
Am J Hum Genet. 2004 Dec;75(6):998-1014.
Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL]-log[P value] = 5.49 at approximately 128 cM), and 17p11 (multipoint NPL-log [P value] >12 at approximately 12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at approximately 12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL-log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes. [Abstract]

Odell JD, Warren RP, Warren WL, Burger RA, Maciulis A.
Association of genes within the major histocompatibility complex with attention deficit hyperactivity disorder.
Neuropsychobiology 1997;35(4):181-6
"The objective was to determine whether a relationship exists among the complement C4B gene, a DR region gene and attention deficit hyperactivity disorder (ADHD). Thirty-one subjects with ADHD, their mothers, all but 5 of their fathers, and 90 normal subjects living in northern Utah were studied. DR and C4B typing were performed by serologic HLA typing techniques and the DNA methods PCR-RFLP. The alleles of 2 genes, the null allele of the C4B gene and the beta 1 allele of the DR gene, encode for products involved in immune function and regulation. Each of these alleles was found to be significantly associated with ADHD. Moreover, approximately 55% of the ADHD subjects carried both of these alleles on 1 of their chromosomes, compared to only 8% of normal controls. Genes related to the immune system may be associated with development of the symptoms of ADHD." [Abstract]

Warren RP, Singh VK, Averett RE, Odell JD, Maciulis A, Burger RA, Daniels WW, Warren WL.
Immunogenetic studies in autism and related disorders.
Mol Chem Neuropathol 1996 May-Aug;28(1-3):77-81
"The major histocompatibility complex comprises a number of genes that control the function and regulation of the immune system. One of these genes, the C4B gene, encodes a product that is involved in eliminating pathogens such as viruses and bacteria from the body. We previously reported that a deficient form of the C4B gene, termed the C4B null allele (no C4B protein produced) had an increased frequently in autism. In this study we attempted to confirm the increased incidence of the C4B null allele in autism and investigated the presence of a C4B null allele in two other childhood disorders, attention-deficit hyperactivity disorder and dyslexia (reading disability). In addition, we explored the relationship of autism to the DR beta 1 gene, a gene located close to the C4B in autism. We confirmed the finding of an increased frequency of the C4B null allele in autism and found that the related disorders also had an increased frequency of this null allele. In addition, two alleles of the DR beta 1 gene also had significantly increased representation in the autistic subjects." [Abstract]

Todd RD, Lobos EA, Sun LW, Neuman RJ.
Mutational analysis of the nicotinic acetylcholine receptor alpha 4 subunit gene in attention deficit/hyperactivity disorder: evidence for association of an intronic polymorphism with attention problems.
Mol Psychiatry 2003;8(1):103-8
"Recent studies suggest the presence of genetically distinct subtypes of attention deficit/hyperactivity disorder (ADHD) and that attention problems can be treated with receptor subtype selective nicotine agonists. In this study, individuals with two independent familial subtypes of ADHD defined by latent class analysis were systematically screened for sequence variations in the coding regions and intron/exon junctions of the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4). Common polymorphisms were used for transmission disequilibrium test (TDT) analyses. A significant association was found for a 5' intron 2 single nucleotide polymorphism and severe inattention problems (P=0.007, effect size=4, 95% CI 1.3-14.1). The location of the polymorphism is compatible with it affecting pre-mRNA stability or splicing." [Abstract]

Kent L, Green E, Holmes J, Thapar A, Gill M, Hawi Z, Fitzgerald M, Asherson P, Curran S, Mills J, Payton A, Craddock N.
No association between CHRNA7 microsatellite markers and attention-deficit hyperactivity disorder.
Am J Med Genet 2001 Dec 8;105(8):686-9
"Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder of childhood that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD. First, nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers, and nonsmokers. Second, ADHD is a significant risk factor for early initiation of cigarette smoking in children and maternal cigarette smoking appears to be a risk factor for ADHD. Finally, animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity. The nicotinic system has previously been studied in schizophrenia where the neuronal nicotinic acetylcholine receptor alpha 7 subunit gene (CHRNA7) has been implicated in decreased P50 inhibition and attentional disturbances in patients with schizophrenia and in many of their nonschizophrenic relatives. Three known microsatellite markers (D15S165, D15S1043, and D15S1360) near the nicotinic acetylcholine alpha 7 receptor gene, CHRNA7, were studied in 206 ADHD parent-proband trios of children aged 5-16 with ADHD according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ < 70) were excluded from the study. Markers D15S165 and D15S1360 were in linkage disequilibrium. The extended Transmission Disequilibrium Test analyses demonstrated no evidence that variation at the microsatellite markers D15S1360, D15S1043, and D15S165 influences susceptibility to ADHD. However, it remains possible that the CHRNA7 gene and other nicotinic system genes may be involved in conferring susceptibility to ADHD." [Abstract]

McCauley E, Feuillan P, Kushner H, Ross JL.
Psychosocial development in adolescents with Turner syndrome.
J Dev Behav Pediatr 2001 Dec;22(6):360-5
"Turner syndrome is a genetic condition in which part or all of the second X chromosome is missing. Our goal in this study was to examine the psychosocial adjustment of a sample of adolescent girls with Turner syndrome. Subjects included 122 girls with a diagnosis of Turner syndrome (TS) and a control group of 108 girls with no genetic disorder or chronic illness. Subjects were 13 to 18 years of age. A battery of questionnaires assessing social, academic, school, and behavioral functioning was administered. TS girls were seen as having significantly more problems in terms of social relationships and school progress and were more likely to meet criteria for attention-deficit hyperactivity disorder than control girls. The TS girls were also rated by a parent as less socially competent (e.g., fewer friends, less time with friends) than the control group. Social difficulties appear to be an area of vulnerability for TS girls. Counseling individuals with Turner syndrome and their families about the need to carefully develop and nurture social skills and relationships may prove useful in advancing the social adaptation of these young women." [Abstract]

Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherlapati R, Shprintzen RJ.
Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder?
Am J Psychiatry 1996 Dec;153(12):1541-7
"OBJECTIVE: The purpose of this study was to conduct a systematic assessment of psychiatric illness in patients diagnosed with velo-cardio-facial syndrome, a genetic syndrome that involves over 40 somatic anomalies, learning disabilities, and behavioral disorders and is associated with a microdeletion on chromosome 22q11. METHOD: Subjects were referred for psychiatric diagnostic evaluation without regard to age or previous psychiatric history. In order to establish DSM-III-R consensus clinical diagnoses for patients who ranged in age from 5 to 34 years, the Diagnostic Interview for Children and Adolescents--Revised or the Structured Clinical Interview for DSM-III-R (SCID) was used. A review of available medical and psychiatric records and a clinical interview performed by two research psychiatrists to validate specific symptoms and syndromes reported in the Diagnostic Interview for Children and Adolescents--Revised and the SCID were used to elucidate the chronological appearance and duration of symptoms. RESULTS: Sixty-four percent (N = 16 of 25) of this unselected series of patients with velo-cardio-facial syndrome met DSM-III-R criteria for a spectrum of bipolar disorders with full syndromal onset in late childhood or early adolescence (mean age at onset = 12 years, SD = 3). In addition, 20% (N = 5) met DSM-III-R criteria for attention deficit hyperactivity disorder (ADHD), while 16% (N = 4) met criteria for attention deficit disorder without hyperactivity. In contrast to previous reports of a high prevalence of schizophrenia, none of the patients was diagnosed with schizophrenia, and only four had psychotic symptoms during a phase of their illness, all in their 20s or 30s. CONCLUSIONS: Given that the prevalence of bipolar disorder in the general population is estimated to be 1.5% and that the average age at onset is 24, these findings support an unusually strong association between velo-cardio-facial syndrome and early-onset bipolar disorder and suggest that a gene deleted at the 22q11 chromosomal locus may be involved in its pathogenesis. If confirmed, these findings may provide a new and fruitful line of investigation into the molecular basis of bipolar spectrum disorders." [Abstract]

Niklasson L, Rasmussen P, Oskarsdottir S, Gillberg C.
Neuropsychiatric disorders in the 22q11 deletion syndrome.
Genet Med 2001 Jan-Feb;3(1):79-84
"PURPOSE: This study was undertaken with a view to establishing the occurrence of neuropsychiatric disorders in the 22q11 deletion syndrome. METHODS: Thirty-two children and young adults with genetically confirmed 22q11 deletion were given comprehensive neuropsychiatric assessments. RESULTS: Altogether, 56% had a neuropsychiatric disorder. Only 6% were of normal IQ and free of physchiatric disorder. Attention-deficit/hyperactivity disorder was diagnosed in 44% and 31% had an autism spectrum problem. In 16% criteria for both these diagnoses were met. Fifty-three percent had mental retardation, often with a test-profile suggesting a nonverbal learning disorder. CONCLUSION: The findings imply that a majority of children and adolescents with 22q11 deletion syndrome are in need of neuropsychiatric assessment and intervention." [Abstract]

Ozonoff S, Williams BJ, Rauch AM, Opitz JO.
Behavior phenotype of FG syndrome: cognition, personality, and behavior in eleven affected boys.
Am J Med Genet 2000 Summer;97(2):112-8
"In this study we examined several behavioral, personality, and cognitive characteristics of boys with FG syndrome. We confirmed high rates of attention and activity level problems, which were described previously. Nine of the 11 patients met criteria for attention deficit/hyperactivity disorder. The boys did not manifest autistic behavior, and none met criteria for an autism spectrum disorder, though their parents reported substantial repetitive behavior. The personalities of the participants often were described as friendly, good-natured, and cheerful, but they did not differ empirically on a standardized measure of personality structure from typically developing comparison children, even after controlling for the effects of IQ. Specifically, higher rates of agreeableness and extraversion were not confirmed, though these constructs do not correspond perfectly with the traits of affability and gregariousness described in earlier published case studies of FG syndrome. In terms of neuropsychological assessment, the boys had relatively less developed language, fine motor, and executive function skills, and visual-spatial abilities were a relative strength. Limitations and suggestions for future research are discussed." [Abstract]

Gross-Tsur V, Landau YE.
[Prader-Willi syndrome: medical, emotional and cognitive facets]
Harefuah 2000 May 15;138(10):833-6, 910
"Prader-Willi syndrome, first described in 1956, is characterized by marked hypotonia, hyperphagia, severe obesity, short stature, hypogonadism, orthopedic problems, breathing-related sleep disorders, mild to moderate mental retardation and behavioral abnormalities. The incidence of this syndrome, an expression of a genetic imprinting error in chromosome 15, is 1:10,000-1:25,000. We describe the medical, emotional and cognitive parameters of 34 patients in our multidisciplinary clinic for Prader-Willi syndrome. Their ages range from 5 months to 40 years and 20 are males. Excessive weight gain started at the age of 6 years, increasing to 170-370% of that predicted by height and age and short stature started after the age of 12. All males have hypogonadism; 6 patients have scoliosis. Breathing-related sleep disorders have occurred in 15. Children above the age of 8 years underwent neuropsychological assessment: half (9/18) have borderline intelligence while a quarter have low-normal intelligence and the remainder mild to moderate mental retardation. Behavioral and social problems are common, and become more prominent during adolescence. ADHD was diagnosed in 10/18." [Abstract]

Stein MA, Weiss RE, Refetoff S.
Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder.
J Dev Behav Pediatr 1995 Dec;16(6):406-11
"Previous studies have demonstrated an association between resistance to thyroid hormone (RTH) and attention-deficit hyperactivity disorder (ADHD). To determine if the neurocognitive characteristics in individuals with RTH are similar to those observed in ADHD, 12 children with RTH from 7 families were matched to 12 children with ADHD without RTH. Subjects were administered standardized intellectual, developmental, and school achievement tests. Parent and teacher ratings of children's hyperactivity and attention were similar for both groups, as were measures of attention, impulsivity, and verbal IQ. Children with RTH displayed lower nonverbal intelligence (performance IQ = 85) and academic achievement (> 1-2 SD below the mean) when compared with those with ADHD only (performance IQ = 99; achievement within 2 SD). Although children with RTH have behavioral characteristics similar to those with ADHD, their significantly weaker abilities of perceptual-organization and lower school achievement suggest a more severe neurobehavioral impairment than ADHD." [Abstract]

Fryns JP.
Aarskog syndrome: the changing phenotype with age.
Am J Med Genet 1992 Apr 15-May 1;43(1-2):420-7
"We describe the Leuven experience with 52 males with Aarskog syndrome particularly with respect to clinical variability, changing phenotype with age, and previously unreported signs. At least 30% of affected males were mentally retarded, two thirds of them at the level of slight mental handicap. Hyperactive behavior and symptoms of attention deficit disorders were frequently observed (61% of the mentally normal and 84% of the mentally subnormal), but regressed completely after the age of 12 to 14 years. The social integration and functioning as adults is satisfactory. Postpubertal males with Aarskog syndrome have only minor remnant manifestations of the prepubertal phenotype, making clinical diagnosis in adults extremely difficult." [Abstract]

Turic D, Langley K, Kirov G, Owen MJ, Thapar A, O'Donovan MC.
Direct analysis of the genes encoding G proteins G alpha T2, G alpha o, G alpha Z in ADHD.
Am J Med Genet. 2004 May 15;127B(1):68-72.
"We have followed up the extensive replicated evidence that the dopamine DRD4 receptor is involved in the aetiology of ADHD by undertaking direct analysis of genes encoding other proteins in this effector system. We prioritised the genes encoding G protein alpha subunits G alpha(T2), G alpha(o), G alpha(Z) as these have been shown to transduce the effects of ligand binding at DRD4. We screened the exons of all three genes for sequence variation in 28 unrelated subjects with ADHD and identified 13 novel polymorphisms. All were tested for possible association with ADHD using a combination of pooled and individual genotyping. The results of our study do not suggest that polymorphisms in these genes contribute to susceptibility to ADHD." [Abstract]

Xu X, Knight J, Brookes K, Mill J, Sham P, Craig I, Taylor E, Asherson P
DNA pooling analysis of 21 norepinephrine transporter gene SNPs with attention deficit hyperactivity disorder: no evidence for association.
Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):115-8.
The norepinephrine system is known to play a role in attentional and cognitive-energetic mechanisms and is thought to be important in attention deficit hyperactivity disorder (ADHD). Stimulant medications are known to alter the activity of norepinephrine as well as dopamine in the synapse and the highly selective norepinephrine reuptake inhibitor, atomoxetine, is an effective treatment for ADHD symptoms. This study set out to investigate whether common polymorphisms within the norepinephrine transporter gene (NET1) are associated with DSM-IV ADHD combined subtype, using a sample that has previously shown association with genes that affect the synaptic release and uptake of neurotransmitters; DAT1 and SNAP-25. We identified 21 single nucleotide polymorphisms (SNPs) from publicly available databases that had minor allele frequencies > or =5% and span the NET1 genomic region, including those analyzed in previous studies of ADHD. DNA pooling was used to screen for associations using two case pools (n = 180 cases) and four control pools (n = 334 controls). We identified three SNPs that showed suggestive evidence for association using either case-control or within family tests of association, however, none of these were significant after adjustment for the number of markers analyzed. We conclude that none of the markers show significant evidence of association with ADHD although we cannot rule out small genetic effects. [Abstract]

Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK, Clasen LS, Sharp WS, Inoff-Germain G, Wavrant-De Vrièze F, Arcos-Burgos M, Straub RE, Hardy JA, Castellanos FX, Rapoport JL
Support for association between ADHD and two candidate genes: NET1 and DRD1.
Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):67-72.
Attention deficit hyperactivity disorder (ADHD) is a common, multifactorial disorder with significant genetic contribution. Multiple candidate genes have been studied in ADHD, including the norepinephrine transporter (NET1) and dopamine D1 receptor (DRD1). NET1 is implicated in ADHD because of the efficacy of atomoxetine, a selective noradrenergic reuptake inhibitor, in the treatment of ADHD. DRD1 is primarily implicated through mouse models of ADHD. DNA from 163 ADHD probands, 192 parents, and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes (5-HT1B, 5-HT2A, 5-HT2C, ADRA2A, CHRNA4, COMT, DAT1, DRD1, DRD4, DRD5, NET1, and SNAP-25). Analyses included case-control and family-based methods, and dimensional measures of behavior, cognition, and anatomic brain magnetic resonance imaging (MRI). Of the 12 genes examined, two showed a significant association with ADHD. Transmission disequilibrium test (TDT) analysis revealed significant association of two NET1 single nucleotide polymorphisms (SNPs) with ADHD (P < or = 0.009); case-control analysis revealed significant association of two DRD1 SNPs with ADHD (P < or = 0.008). No behavioral, cognitive, or brain MRI volume measurement significantly differed across NET1 or DRD1 genotypes at an alpha of 0.01. This study provides support for an association between ADHD and polymorphisms in both NET1 and DRD1; polymorphisms in ten other candidate genes were not associated with ADHD. Because family-based and case-control methods gave divergent results, both should be used in genetic studies of ADHD. [Abstract]

De Luca V, Muglia P, Jain U, Kennedy JL.
No evidence of linkage or association between the norepinephrine transporter (NET) gene MnlI polymorphism and adult ADHD.
Am J Med Genet. 2004 Jan 1;124B(1):38-40. [Abstract]

Yang L, Wang YF, Li J, Faraone SV
Association of norepinephrine transporter gene with methylphenidate response.
J Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1154-8.
OBJECTIVE: This study aimed to explore the association between alleles of the norepinephrine transporter gene and the methylphenidate response. METHOD: Chinese Han youths with attention-deficit/hyperactivity disorder recruited in the Outpatient Department of the Institute of Mental Health from 2001 to 2004 were treated with methylphenidate in doses of 0.45 to 0.60 mg/kg per day. Behavior changes were measured by the ADHD Rating Scale-IV when optimal doses were reached. The single-nucleotide polymorphic allele of norepinephrine transporter gene G1287A was used as the genetic marker, and the genotypes were identified by restriction fragment length polymorphism analysis. RESULTS: A significant association was found between norepinephrine transporter gene G1287A genotypes and response to methylphenidate for hyperactive-impulsive subscale scores (mean score reduction was 7.15 and 6.94 for G/G and G/A genotype, respectively, and 2.13 for A/A; p = .012) but not inattentive scores. CONCLUSIONS: These findings suggest an association between the G1287A polymorphism of the norepinephrine transporter gene and variation in methylphenidate response. Further work is needed to confirm this finding and to assess its generalization to other ethnic groups. [Abstract]

Bellgrove MA, Domschke K, Hawi Z, Kirley A, Mullins C, Robertson IH, Gill M
The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD.
Exp Brain Res. 2005 Jun;163(3):352-60.
ADHD is a highly heritable psychiatric disorder of childhood. A functional polymorphism (Val158Met) of the catechol-O-methyltransferase (COMT) gene has attracted interest as a candidate gene for ADHD. The high-activity valine variant of this polymorphism degrades prefrontal dopamine three to four times more quickly than the low-activity methionine variant and could therefore contribute to the proposed hypodopaminergic state in ADHD. Here we tested for association of this polymorphism with ADHD and examined its influence on prefrontal cognition in ADHD. We have previously reported no association of the Val158Met COMT gene polymorphism in 94 Irish ADHD families (Hawi et al. (2000) Am J Med Genet 96:282-284). Here we re-examined this finding with an extended sample of 179 ADHD cases using a family control design. We also examined the performance of children and adolescents with ADHD (n = 61) on a standardised test of sustained attention. Analysis confirmed the absence of an association between the Val158Met COMT gene polymorphism and the clinical phenotype of ADHD. COMT genotype, however, affected prefrontal cognition in ADHD: ADHD children who were homozygous for the valine variant had significantly better sustained attention than those ADHD children possessing at least one copy of the methionine variant. Children possessing the methionine variant performed significantly below age-related norms on tests of sustained attention. Contrary to expectations, the methionine variant of the Val158Met COMT gene polymorphism impaired prefrontally-mediated cognition in ADHD. This effect may be understood by positing a hyper-functioning of prefrontal dopaminergic systems. Against this background, the slower clearance of dopamine associated with the methionine variant of the COMT gene polymorphism may be disadvantageous to cognition in ADHD. [Abstract]

Taerk E, Grizenko N, Ben Amor L, Lageix P, Mbekou V, Deguzman R, Torkaman-Zehi A, Ter Stepanian M, Baron C, Joober R
Catechol-O-methyltransferase (COMT) Val108/158 Met polymorphism does not modulate executive function in children with ADHD.
BMC Med Genet. 2004 Dec 21;530.
BACKGROUND: An association has been observed between the catechol-O-methyltransferase (COMT) gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC), and neuropsychological task performance in healthy and schizophrenic adults. Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD) are mediated by prefrontal dopamine (DA) mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children. METHODS: The Val108/158 Met polymorphism of the COMT gene was genotyped in 118 children with ADHD (DSM-IV). The Wisconsin Card Sorting Test (WCST), Tower of London (TOL), and Self-Ordered Pointing Task (SOPT) were employed to evaluate executive functions. Neuropsychological task performance was compared across genotype groups using analysis of variance. RESULTS: ADHD children with the Val/Val, Val/Met and Met/Met genotypes were similar with regard to demographic and clinical characteristics. No genotype effects were observed for WCST standardized perseverative error scores [F2,97 = 0.67; p > 0.05], TOL standardized scores [F2,99 = 0.97; p > 0.05], and SOPT error scores [F2,108 = 0.62; p > 0.05]. CONCLUSIONS: Contrary to the observed association between WCST performance and the Val108/158 Met polymorphism of the COMT gene in both healthy and schizophrenic adults, this polymorphism does not appear to modulate executive functions in children with ADHD. [Abstract] [Full Text]

Qian Q, Wang Y, Zhou R, Li J, Wang B, Glatt S, Faraone SV.
Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism.
Am J Med Genet 2003 Apr 1;118B(1):103-9
"Attention deficit hyperactivity disorder (ADHD) is the most common childhood-onset behavioral disorder. Boys are more often affected than girls. Family, twin, and adoption studies have supported a strong genetic basis. Some studies show that a catechol-O-methyltransferase (COMT) polymorphism affecting enzyme activity was associated with personality characteristics and diseases, such as novelty-seeking personality, substance abuse, and heroin addiction, whose features are similar to ADHD or are associated with ADHD. These findings suggest that the COMT gene may be a candidate gene for ADHD. TDT, HHRR, and case-control association studies were conducted within a sample of 202 nuclear ADHD families, 340 ADHD cases, and 226 controls in the Han Chinese population. Diagnoses and ADHD subtypes were ascertained according to DSM-IV criteria using American Clinical Diagnostic Interviewing Scales. The HHRR analysis suggested that the low enzyme-activity COMT Met allele was preferentially transmitted to ADHD boys (160 trios, chi(2) = 3.858, P = 0.05, df = 1) but not girls. This association is particularly pronounced among male ADHD probands without any comorbidity (50 trios, HHRR: chi(2) = 5.128, P = 0.024, df = 1; TDT: chi(2) = 4.558, P = 0.033, df = 1), especially the ADHD-I subtype (32 trios, HHRR: chi(2) = 5.792, P = 0.016, df = 1; TDT: chi(2) = 5.333, P = 0.021, df = 1). The case-control study revealed that the Val allele was more frequent in females meeting ICD-10 or DSM-IV criteria for ADHD than in female controls (86 and 79.5%, respectively, chi(2) = 4.059, P = 0.044, df = 1). Although these results suggest the COMT gene exerts some influence on the risk for ADHD in the Han Chinese population, given the potential for Type I error, these findings require replication before drawing definitive conclusions." [Abstract]

Turic D, Williams H, Langley K, Owen M, Thapar A, O'Donovan MC
A family based study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD).
Am J Med Genet B Neuropsychiatr Genet. 2005 Feb 5;133(1):64-7.
Neurobiological studies have suggested that altered dopaminergic function may contribute to the etiology of attention deficit hyperactivity disorder (ADHD). The gene encoding catechol-O-methyltransferase (COMT) is an attractive candidate for ADHD susceptibility as it plays a major role in the degradation of dopamine. Moreover, a functional Val158Met polymorphism in COMT that alters the activity of the encoded protein has been strongly implicated in frontal lobe function, with the high activity Valine allele being associated with poorer performance, and ADHD is thought to involve fronto-striatal pathways. We have examined this functional variant for association with ADHD in a family based association sample comprising 279 probands and their parents. We have also examined two other markers in the COMT gene (rs737865, rs165599) which, together with the Val/Met variant, have recently been shown to be associated with altered COMT expression rather than enzyme activity. No evidence for association was observed with any single marker or haplotype in a sample of 279 affected children and their parents. [Abstract]

Zhang X, Ruan L, Le Y, Zhang Y.
[Association analysis between attention-deficit hyperactivity disorder and Val158Met polymorphism of catechol-O-methyltransferase gene]
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2003 Aug 10;20(4):322-4.
"OBJECTIVE: To investigate the association between attention-deficit hyperactivity disorder (ADHD) in Han Chinese children and Val158Met polymorphism of catechol-O-methyltransferase (COMT) gene caused by the missense mutation of G158A in exon 4. METHODS: By using polymerase chain reaction-restriction fragment length polymorphisms the Val158Met polymorphism of COMT gene was tested in 117 children with the diagnosis of ADHD as defined by DSM-IV and in 105 healthy controls living in Shanghai. RESULTS: The frequencies of A allele were 25.21% and 23.81% in the ADHD group and the health controls respectively, which showed no significant difference between the two groups (Chi-square=0.5197, P>0.05). There was also no significant difference in the distribution of all genotypes of COMT gene between the ADHD patients and the controls (P>0.05). CONCLUSION: It was suggested that for the Han Chinese children with ADHD in this study, there was no association between ADHD and Val158Met polymorphism of COMT gene." [Abstract]

Mills S, Langley K, Van den Bree M, Street E, Turic D, Owen MJ, O'Donovan MC, Thapar A.
No evidence of association between Catechol-O-Methyltransferase (COMT) Val158Met genotype and performance on neuropsychological tasks in children with ADHD: a case-control study.
BMC Psychiatry. 2004 Jun 7;4(1):15.
"BACKGROUND: Several studies have suggested an association between the functional Val158Met polymorphism in the Catechol-O-Methyltransferase (COMT) gene and neurocognitive performance. Two studies showed that subjects with the low activity Met allele performed better on the Wisconsin Card Sorting Test (WCST) and another study found an effect on processing speed and attention. METHODS: We set out to examine the association between the Val158Met polymorphism and performance on neurocognitive tasks including those tapping working memory, attention and speed, impulsiveness and response inhibition in a sample of 124 children with ADHD. Task performance for each genotypic group was compared using analysis of variance. RESULTS: There was no evidence of association with performance on any of the neurocognitive tasks. CONCLUSIONS: We conclude that Val158Met COMT genotype is not associated with neurocognitive performance in our sample." [Full Text]

Rietveld MJ, Hudziak JJ, Bartels M, van Beijsterveldt CE, Boomsma DI.
Heritability of attention problems in children: longitudinal results from a study of twins, age 3 to 12.
J Child Psychol Psychiatry. 2004 Mar;45(3):577-88.
"BACKGROUND: Twin studies of childhood behavior problems support the conclusion that individual differences in impulsivity, hyperactivity, and inattention are largely due to genetic influences. Non-genetic variation is due to environmental influences that are unique to the individual, and possibly to rater contrast effects. In the present longitudinal twin study, we report on the size of genetic and environmental effects on individual differences in attention problems at ages 3, 7, 10 and 12 years. METHODS: Mothers were asked to complete the CBCL for their twin offspring when the children were 3 (n = 11,938), 7 (n = 10,657), 10 (n = 6,192), and 12 years old (n = 3,124). We focus on the Overactivity (OA) scale in the Child Behavior Checklist (CBCL/2-3), and on the Attention Problem (AP) scale of the CBCL/4-18. The data were analyzed using longitudinal structural equation modeling. RESULTS: Broad heritability of OA and AP is estimated at nearly 75%, at each age. A contrast effect was observed at age 3 only. The results revealed less stability of OA at age 3 to AP at age 7 (r = .40), compared to the stability from AP at age 7 and beyond (r = .70). Genetic effects explained between 76% and 92% of the covariance between OA and AP. CONCLUSIONS: OA and AP are highly heritable at all ages in both genders. The same set of genes appears to be expressed in boys and girls. The size of genetic and environmental contributions remains the same across the ages studied. Stability in OA and AP is accounted for by genetic influences. Children who do not display OA or AP at a given age are unlikely to develop these problems at a subsequent age." [Abstract]

Loo SK, Fisher SE, Francks C, Ogdie MN, MacPhie IL, Yang M, McCracken JT, McGough JJ, Nelson SF, Monaco AP, Smalley SL.
Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: unique and shared genetic effects.
Mol Psychiatry. 2004 May;9(5):485-93.
"Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are common highly heritable disorders of childhood, which frequently co-occur. Data from twin and family studies suggest that this overlap is, in part, due to shared genetic underpinnings. Here, we report the first genome-wide linkage analysis of measures of reading ability in children with ADHD, using a sample of 233 affected sibling pairs who previously participated in a genome-wide scan for susceptibility loci in ADHD. Quantitative trait locus (QTL) analysis of a composite reading factor defined from three highly correlated reading measures identified suggestive linkage (multipoint maximum lod score, MLS>2.2) in four chromosomal regions. Two regions (16p, 17q) overlap those implicated by our previous genome-wide scan for ADHD in the same sample: one region (2p) provides replication for an RD susceptibility locus, and one region (10q) falls approximately 35 cM from a modestly highlighted region in an independent genome-wide scan of siblings with ADHD. Investigation of an individual reading measure of Reading Recognition supported linkage to putative RD susceptibility regions on chromosome 8p (MLS=2.4) and 15q (MLS=1.38). Thus, the data support the existence of genetic factors that have pleiotropic effects on ADHD and reading ability--as suggested by shared linkages on 16p, 17q and possibly 10q--but also those that appear to be unique to reading--as indicated by linkages on 2p, 8p and 15q that coincide with those previously found in studies of RD. Our study also suggests that reading measures may represent useful phenotypes in ADHD research. The eventual identification of genes underlying these unique and shared linkages may increase our understanding of ADHD, RD and the relationship between the two." [Abstract]

Todd RD, Joyner CA, Ji TH, Sun L, Reich W, Neuman RJ.
Family factors and sampling approach differentially influence attention deficit/hyperactivity disorder subtypes.
Mol Psychiatry. 2004 Mar;9(3):260-3.
"A widely used statistical method to test for genetic association is the transmission disequilibrium test (TDT) using two parent-proband trios. West et al(1) have presented evidence from clinically ascertained ADHD families that children from trios were less likely to have DSM-IV combined subtype ADHD and conduct disorder. They suggest that the exclusion of parent-proband duos could reduce the power of the TDT and similar tests to detect susceptibility genes for this subtype of ADHD. We sought to test this hypothesis in a population-based sample of twin families, while controlling for the effects of other proband and family characteristics in a multivariant logistic regression framework using both latent class and DSM-IV ADHD subtype definitions. For both latent class and DSM-IV defined combined and inattentive ADHD, sex of the proband and comorbid conduct disorder or oppositional defiant disorder, significantly predicted diagnosis. For latent class and DSM-IV defined combined subtype, younger age also significantly predicted ADHD subtype. Latent class and DSM-IV defined combined subtype ADHD with comorbid conduct disorder was significantly less common in children from trios while conduct disorder without ADHD did not differ in frequency between families with zero, one or two participating parents." [Abstract]

Biederman J, Faraone SV.
The Massachusetts General Hospital studies of gender influences on attention-deficit/hyperactivity disorder in youth and relatives.
Psychiatr Clin North Am. 2004 Jun;27(2):225-32.
"With the single exception of SUDs, no statistically significant gender-by ADHD interactions were identified in the multiple, outcomes evaluated. These results suggest that with the exception of SUDs, ADHD expresses itself similarly in boys and girls relative to comparison subjects of the same gender, indicating that ADHD-associated impairments are correlates of ADHD in both genders. Gender differences, such as the higher prevalence of symptoms of inattention and lower rates of comorbidity with disruptive behavior disorders, major depression, and learning disability, were identified among the ADHD subjects. Because these differences were caused by the main effects of gender rather than effect modification of ADHD by gender, these findings indicate that girls were at the same relative risk for these adverse outcomes as boys, but that female gender resulted in a different clinical presentation than that affecting boys.The single statistically significant gender-by-ADHD interaction identified was the association between ADHD and SUDs (alcohol or drug abuse or dependence). ADHD in females was a more serious risk factor for SUDsthan it was in males was an unanticipated and surprising finding. In light of ongoing concerns regarding ADHD as a putative risk factor of SUDs [12],this finding may indicate that girls are particularly at risk in early adolescence. Considering that the age of onset of ADHD and SUDs are separated by at least a decade [13.14], this finding would support targeting of substance abuse prevention programs to girls with ADHD.Furthermore, results show that although the combined type of ADHDwas the predominant type in both genders, girls with ADHD were twice as likely as boys with ADHD to manifest the predominantly inattentive type of the disorder. Because symptoms of inattention are more covert than those of hyperactivity and impulsivity, their higher prevalence in girls with ADHDrelative to boys also may explain partially the markedly higher male-to-female ratios in referred versus nonreferred samples of children withADHD.This work also showed that the pattern of transmission of ADHD and comorbid disorders is not influenced by the proband's gender. This is true for the type of disorder transmitted and the degree of risk to relatives. The finding of no interactions between proband ADHD diagnosis and pro-band gender clearly rejects the idea that gender differences in comorbid disorders can be attributed to genes or other familial causes. Prior work had shown this to be true for the diagnosis of ADHD in relatives [15-20].Thus, gender and ADHD appear to be independent risk factors for comorbid psychopathology and for the familial transmission of comorbid psychopathology.In summary, these results suggest that gender was a limited effect modifier of ADHD as a risk factor for ADHD-associated dysfunction in referred children and adolescents. Gender, however, did impact the clinical presentation of the disorder. This was largely because girls with ADHDwere less likely than boys to have comorbid disruptive behavior problems and higher prevalence of symptoms of inattention. Because these features could result in gender-based referral bias unfavorable to girls, more work is needed in referred and nonreferred samples of youth with ADHD to more fully assess this issue. These results also showed similar patterns in the familial transmission of comorbid disorders in families of boys and girls with ADHD. Thus, although ADHD is associated with the familial trans-mission of comorbid disorders, the pattern of transmission is not influenced by the proband's gender. These similar patterns provide further evidence for the idea that, when ADHD is diagnosed in girls it corresponds to the same disorder diagnosed in boys." [Abstract]

Barr CL, Shulman R, Wigg K, Schachar R, Tannock R, Roberts W, Malone M, Kennedy JL.
Linkage study of polymorphisms in the gene for myelin oligodendrocyte glycoprotein located on chromosome 6p and attention deficit hyperactivity disorder.
Am J Med Genet 2001 Apr 8;105(3):250-4
"Family and twin studies have shown that there is a substantial genetic contribution to both reading disabilities (RD) and attention deficit hyperactivity disorder (ADHD), and recent twin studies have suggested that the overlap between these phenotypes is largely due to common genetic influences. Studies using a linkage approach to search for genes for susceptibility to RD and ADHD have identified regions linked to each of these phenotypes separately, with recent studies suggesting that some chromosomal regions may contribute to both. Linkage to the human leukocyte antigen (HLA) region has been targeted in particular for RD and ADHD, as both of these disorders have been suggested to be autoimmune. Linkage to the HLA region of 6p for RD has now been reported by several groups. Alleles at two genes in the HLA (C4B and DRB1) have also been reported to be associated with ADHD, prompting one investigator to suggest a possible connection between the linkage of RD and ADHD to this region. The location of the gene for myelin oligodendrocyte glycoprotein (MOG), in the region of 6p with the strongest evidence for linkage to RD, and its proposed role as a minor component of myelin in the central nervous system suggest that it may be a factor in neuronal functioning and therefore a candidate for RD and ADHD. In this study, we tested the gene for linkage to ADHD by genotyping two polymorphisms in the MOG gene-a dinucleotide repeat located upstream from the MOG transcription start site and a Val145Ile substitution in exon 3-in a sample of 104 nuclear families identified through a proband with ADHD. We examined the transmission of the alleles of the Val145Ile and the dinucleotide repeat polymorphisms using the transmission disequilibrium test. We did not observe biased transmission of the alleles at either polymorphism to ADHD probands or siblings. Our findings using this sample do not support the role of the MOG gene in ADHD." [Abstract]

Rohde LA, Szobot C, Polanczyk G, Schmitz M, Martins S, Tramontina S
Attention-deficit/hyperactivity disorder in a diverse culture: do research and clinical findings support the notion of a cultural construct for the disorder?
Biol Psychiatry. 2005 Jun 1;57(11):1436-41.
There is still some debate in the literature whether Attention-Deficit Disorder/Hyperactivity (ADHD) is best conceptualized as a biological disorder or if it is best understood as a cultural construct. This review aims to contribute to disentangle this issue assessing clinical and research data on ADHD in a complete diverse culture from a developing country. We performed a systematic computerized review of the literature on ADHD in Brazil. All investigations were included if dealing with ADHD prevalence, etiology, symptomatological construct, or treatment. Findings were compared to those from studies in developed countries. The prevalence rates of ADHD (5.8% using DSM-IV criteria, 1.5% using ICD-10), the bi-dimensional factor construct extracted from factor analyses (inattention and hyperactivity/impulsivity), the pattern of ADHD comorbidity in clinical samples, the family genetic data suggesting a 39% family transmission in clinical samples and the role of some potential candidate genes in dopaminergic and noradrenergic systems, as well as data on the efficacy of methylphenidate in the disorder are all very similar to findings from developed countries. Taken together, these findings suggest that ADHD is not a cultural construct, reinforcing the importance of applying similar research methodology in different cultures to make findings comparable. [Abstract]

Acosta MT, Arcos-Burgos M, Muenke M.
Attention deficit/hyperactivity disorder (ADHD): complex phenotype, simple genotype?
Genet Med. 2004 Jan-Feb;6(1):1-15.
"Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation and/or assortment but exhibiting a preferential familial clustering that cannot be explained by cultural or environmental causes. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and probably the most controversial. ADHD has been considered a complex genetic trait based upon the absence of a clear-cut boundary between affected and unaffected status. Furthermore, its high comorbidity with other disorders strongly suggests complex epistatic or pleiotropic effects acting in common with the environmental influences. This implies that the same gene or genes is or are associated with different and concurrently occurring phenotypes. In this study, we will review clinical and epidemiological aspects related to the ADHD phenotype, which are considered either as categorical or continuous traits. We also will discuss genetic models underlying the complexity of this behavioral phenotype and the probable role of epistatic interactions between major genes contributing to the ADHD phenotype." [Abstract]

Doyle AE, Faraone SV, Seidman LJ, Willcutt EG, Nigg JT, Waldman ID, Pennington BF, Peart J, Biederman J
Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD?
J Child Psychol Psychiatry. 2005 Jul;46(7):774-803.
BACKGROUND: Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or phenotypes that are more closely linked to the neurobiological substrate of a disorder, offer the potential to address these two issues simultaneously (Freedman, Adler, & Leonard, 1999). Thus far, potential endophenotypes for ADHD have not been systematically studied. METHOD: The current paper reviews evidence supporting the use of deficits on neurocognitive measures of executive functions for this purpose. RESULTS: Such deficits are a correlate of ADHD and show preliminary evidence of heritability and association with relevant candidate genes. Nonetheless, studies that have assessed the familial and genetic overlap of neurocognitive impairments with ADHD have yielded inconsistent results. CONCLUSIONS: In order for executive function deficits to be used as an endophenotype for ADHD, we recommend greater attention to the neurocognitive heterogeneity of this disorder and to the precision of measurement of the neuropsychological tests employed. We also discuss empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD. [Abstract]

Doyle AE, Willcutt EG, Seidman LJ, Biederman J, Chouinard VA, Silva J, Faraone SV
Attention-deficit/hyperactivity disorder endophenotypes.
Biol Psychiatry. 2005 Jun 1;57(11):1324-35.
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such "endophenotypes" have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power. [Abstract]

Sklar P
Principles of haplotype mapping and potential applications to attention-deficit/hyperactivity disorder.
Biol Psychiatry. 2005 Jun 1;57(11):1357-66.
Approaches to the study of common, complex genetic disorders like attention-deficit/hyperactivity disorder (ADHD) are evolving rapidly. Traditional linkage and association mapping each have distinct roles to play. Rapid advances in genomic information and technologies make association studies more attractive, including the possibility in the near future of whole genome association scans. This review covers the following broad topics: 1) the principles of linkage and association analyses as they apply to ADHD, and 2) the implications of genome architecture for association studies of complex diseases like ADHD. The structure of linkage disequilibrium is approached through review of the statistical measures of allelic associations and their relationship to observed haplotypes. The patterns of haplotypes across the human genome are discussed, as well as the implications of linkage disequilibrium mapping for association studies in general and ADHD specifically. Finally, the extent to which the allelic architecture of a candidate ADHD gene is publicly available and the web resources to access this information are covered. Today, the wealth of polymorphism data available on the worldwide web enables researchers to focus powerful methodologic tools on candidate genes and regions of interest. Coupling this with larger patient collections and more refined phenotyping will move forward the identification of disease-associated polymorphisms and ultimately the development of genetically based pharmaceuticals and diagnostic tests. [Abstract]

Kuntsi J, Rijsdijk F, Ronald A, Asherson P, Plomin R
Genetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood.
Biol Psychiatry. 2005 Mar 15;57(6):647-54.
BACKGROUND: The high heritability of the core symptoms of attention-deficit/hyperactivity disorder (ADHD) has been repeatedly demonstrated, but few studies to date have investigated the extent to which the same genetic influences operate across development or new genes emerge at different developmental periods. METHODS: We report data from a large, population-based study of approximately 4,000 twin pairs, who have been followed up from early to middle childhood. RESULTS: Parents' ratings of ADHD symptoms showed moderate stability across the ages, which was mainly due to shared genetic influences. There was also evidence of additional genetic influences, which were not shared with those acting earlier on, emerging at later age periods. The contribution of environmental influences to the stability of the ADHD symptoms over time was small. Parents' ratings on the Conners' DSM-IV ADHD subscale at the last assessment point, at an average age of 8 years, did not show the rater contrast effects that were observed in the parents' ratings at earlier ages with briefer measures. Similar estimates of genetic and environmental influences were obtained for girls and boys. CONCLUSIONS: We discuss the implications of the findings for molecular genetic studies on ADHD symptomatology. [Abstract]

Larsson JO, Larsson H, Lichtenstein P
Genetic and environmental contributions to stability and change of ADHD symptoms between 8 and 13 years of age: a longitudinal twin study.
J Am Acad Child Adolesc Psychiatry. 2004 Oct;43(10):1267-75.
OBJECTIVE: To study the genetic and environmental contributions to stability and change of attention-deficit/hyperactivity disorder (ADHD) symptoms between 8 and 9 and 13 and 14 years of age. METHOD: The sample included 1,480 twin pairs born in Sweden between May 1985 and December 1986. At wave 1 in 1994, when twins were 8-9 years old, 1,106 (75%) of the parents responded to a mailed questionnaire, and at wave 2 when the twins were 13-14 years old, 1,063 (73%) responded. A checklist with 14 items based on the 14 DSM-III-R symptoms for ADHD was completed. Structural equation modeling was used to analyze the data. RESULTS: A relatively high stability of ADHD symptoms over this 5-year period was found. This continuity was mainly due to the same genetic effects operating at both points in time. Change in symptoms between childhood and early adolescence was to a large extent due to new genetic effects in early adolescence but also due to new nonshared environmental effects that became important during adolescence. CONCLUSIONS: The genetic stability highlights the importance of the continuing search for genes and endophenotypes of ADHD. [Abstract]

Yeh M, Morley KI, Hall WD.
The policy and ethical implications of genetic research on attention deficit hyperactivity disorder.
Aust N Z J Psychiatry. 2004 Jan-Feb;38(1-2):10-9.
"OBJECTIVE: To review the policy and ethical implications of recent research on the molecular genetics of attention deficit hyperactivity disorder (ADHD). METHOD: MEDLINE and psycINFO database searches were used to identify studies on the genetics of ADHD. The implications of replicated candidate genes are discussed. RESULTS: The findings for most genes have been inconsistent but several studies have implicated the genes in the dopaminergic pathway in the aetiology of ADHD. CONCLUSIONS: The current evidence on the genetics of ADHD is insufficient to justify genetic screening tests but it will provide important clues as to the aetiology of ADHD. Genetic information on susceptibility to ADHD has the potential to be abused and to stigmatize individuals. Researchers and clinicians need to be mindful of these issues in interpreting and disseminating the results of genetic studies of ADHD." [Abstract]

McGough JJ
Attention-deficit/hyperactivity disorder pharmacogenomics.
Biol Psychiatry. 2005 Jun 1;57(11):1367-73.
Although the efficacy of medications for attention-deficit/hyperactivity disorder (ADHD) is well demonstrated in clinical trials, substantial numbers of patients fail to remain on therapy, and there is tremendous variability in tolerability and treatment acceptance. The emerging science of pharmacogenomics seeks to identify patterns of genetic variation that will direct individually tailored treatment regimens and enhance long-term adherence. For this review, existing studies in ADHD pharmacogenomics were reviewed to assess current knowledge and provide a basis for planning future research. Twelve studies were identified. The majority investigated the role of candidate genes in predicting clinical response to methylphenidate. The most frequently studied is DAT1, although findings are inconsistent, with the 10-repeat polymorphism predicting both increased and decreased symptom reduction in various reports. Other candidates include DRD4, DRD5, DBH, 5HTT, SNAP-25, and COMT. One study was based on quantitative trait analyses in a genome-wide scan. Although interest in ADHD pharmacogenomics is encouraging, preliminary studies have been limited by small sample sizes, inconsistent research designs, retrospective reports, and a focus on symptom response. Future studies should emphasize large, prospective trials, assess multiple medications in individual subjects, and consider a full range of pharmacodynamic and pharmacokinetic outcomes. [Abstract]

Wigg K, Zai G, Schachar R, Tannock R, Roberts W, Malone M, Kennedy JL, Barr CL.
Attention deficit hyperactivity disorder and the gene for dopamine Beta-hydroxylase.
Am J Psychiatry 2002 Jun;159(6):1046-8
"OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) has been shown to be highly heritable, and recent molecular genetics studies have focused on candidate genes in the dopaminergic and noradrenergic systems. One recent study reported an association of an allele of the TaqI polymorphism located in the fifth intron of the gene for dopamine beta-hydroxylase (DBH). The authors' goal was to replicate this finding. METHOD: The authors investigated the linkage of the alleles and haplotypes of three polymorphisms at the DBH locus in 117 nuclear families with ADHD. RESULTS: No significant evidence was found for linkage of the TaqI alleles or haplotypes in the 117 families. However, the authors observed some evidence for biased transmission of the same allele of the TaqI polymorphism, as previously reported. CONCLUSIONS: These findings suggest that the gene for DBH should be investigated further." [Abstract] [Full Text]

Roman T, Schmitz M, Polanczyk GV, Eizirik M, Rohde LA, Hutz MH.
Further evidence for the association between attention-deficit/hyperactivity disorder and the dopamine-beta-hydroxylase gene.
Am J Med Genet 2002 Mar 8;114(2):154-8
"Attention-deficit/hyperactivity disorder (ADHD) is a very common and heterogeneous psychiatric disorder of childhood with marked inattentive, hyperactive, and impulsive symptoms. The DBH gene, the locus that encodes the enzyme dopamine-beta-hydroxylase (DbetaH), seems to be an important candidate gene for association studies, since DbetaH catalyzes the conversion of dopamine to norepinephrine. The aim of this study was to test for association between the DBH gene and ADHD in a sample of 88 Brazilian nuclear families. Haplotype relative risk (HRR) analysis of the DBH TaqI restriction site polymorphism showed a preferential transmission of the TaqI A2 allele in our whole ADHD sample (chi(2)=3.61, one-tailed P=0.03). The significant effect of the A2 allele was stronger when only families with no ADHD parental diagnosis were considered (chi(2)=5.42, one-tailed P=0.01). Our results suggest a contribution of this gene to ADHD susceptibility, partially replicating previous findings that have demonstrated an association between the DBH TaqI A2 allele and ADHD." [Abstract]

Inkster B, Muglia P, Jain U, Kennedy JL.
Linkage disequilibrium analysis of the dopamine beta-hydroxylase gene in persistent attention deficit hyperactivity disorder.
Psychiatr Genet. 2004 Jun;14(2):117-120.
"Numerous family, twin and adoption studies have reported a strong genetic component for attention deficit hyperactivity disorder (ADHD). In addition, an extensive amount of literature has implicated abnormalities of the dopaminergic system. In view of this evidence, genes that influence dopaminergic transmission have become prime candidates for molecular genetic investigations of ADHD. There are currently three studies (;; ) that have found an association between the dopamine beta-hydroxylase gene (DBH) TaqI 2 allele and childhood ADHD. As such, we tested for association of the DBH TaqI 2 allele in two independent samples of patients with the persistent variant of ADHD. These consisted of 97 nuclear families, and 112 adult cases with controls carefully matched according to gender, age and ethnicity. Transmission Disequilibrium Test analysis revealed weak over-transmission of the 2 allele (35 transmissions versus 27 non-transmissions; chi = 1.03, 1 degree of freedom, P=0.31). The case-control sample did not support previous findings since the 2 allele was more frequent in our control sample (137 versus 116; chi=3.63, 1 degree of freedom, P=0.057). Taken together, these results do not provide support for a role of the DBH TaqI marker in our persistent ADHD samples." [Abstract]

Smith KM, Daly M, Fischer M, Yiannoutsos CT, Bauer L, Barkley R, Navia BA.
Association of the dopamine beta hydroxylase gene with attention deficit hyperactivity disorder: Genetic analysis of the Milwaukee longitudinal study.
Am J Med Genet 2003 May 15;119B(1):77-85
"Attention deficit hyperactivity disorder (ADHD) is a highly heritable and common disorder that partly reflects disturbed dopaminergic function in the brain. Recent genetic studies have shown that candidate genes involved in dopamine signaling and metabolism contribute to ADHD susceptibility. We have initiated genetic studies in a unique cohort of 158 ADHD and 81 control adult subjects who have been followed longitudinally since childhood in the Milwaukee study of ADHD. From this cohort, genetic analysis was performed in 105 Caucasian subjects with ADHD and 68 age and ethnicity-matched controls for the DRD4 exon 3 VNTR, the SLC6A3 (DAT1) 3' UTR VNTR, dopamine beta hydroxylase (DBH) TaqI A polymorphism, and the DBH GT microsatellite repeat polymorphism that has been quantitatively associated with serum levels of DBH activity, but not previously studied in ADHD. Results indicate a significant association between the DBH TaqI A1 allele and ADHD (P = 0.018) with a relative risk of 1.33. The DBH GT repeat 4 allele, which is associated with high serum levels of DBH, occurred more frequently in the ADHD group than controls, but the difference did not reach statistical significance. Associations were not found with the SLC6A3 10 repeat or DRD4 7 repeat alleles. These results indicate that the DBH TaqI A allele, or another polymorphism in linkage disequilibrium with this allele, may confer increased susceptibility towards ADHD." [Abstract]

Bhaduri N, Sinha S, Chattopadhyay A, Gangopadhyay PK, Singh M, Mukhopadhyay KK
Analysis of polymorphisms in the dopamine Beta hydroxylase gene: association with attention deficit hyperactivity disorder in Indian children.
Indian Pediatr. 2005 Feb;42(2):123-9.
OBJECTIVE: To study the association of Attention Deficit Hyperactivity Disorder (ADHD) and polymorphism in the dopamine beta hydroxylase (DBH) gene in Indian ADHD cases. Subjects: Forty one ADHD cases were diagnosed as per the DSM-IV-TR criteria and evaluated by Conners Parents and Teachers Rating Scale and Wechslers Intelligence Scale for Children. METHODS: Genomic DNA was amplified for exon 2 *444g/a and intron 5 (Taq I) polymorphism in the DBH gene followed by restriction fragment length polymorphism (RFLP) analysis. Haplotype-based haplotype relative risk (HHRR) was analyzed to ascertain the transmission pattern of these two polymorphisms in ADHD cases. Linkage disequilibrium (LD) between the two polymorphisms was calculated using EH+ and 2LD programs. RESULTS: In the limited number of samples analyzed, a slight increase in transmission of the 444a allele in ADHD subjects was observed for DBH 444g/a. The intron 5 (Taq I) polymorphism showed no significant association with ADHD in these cases. Strong disequilibrium was observed between DBH444g/a and intron 5 (Taq I) polymorphism. CONCLUSION: This is the first molecular genetic study on ADHD in Indian subjects exploring transmission of polymorphisms in the DBH gene. Preliminary investigation shows a trend towards association between the transmission of DBH444a allele and ADHD. No association was noticed between transmission of intron 5 (Taq I) polymorphism and ADHD in the Indian subjects. Presence of strong LD may point towards co-segregation of these two polymorphisms more often than expected. [Abstract] [Full Text]

Zhang HB, Wang YF, Li J, Wang B, Yang L.
[Association of dopamine beta-hydroxylase polymorphism with attention deficit hyperactivity disorder in children]
Beijing Da Xue Xue Bao. 2004 Jun 18;36(3):290-3.
"OBJECTIVE: To study the association of dopamine beta-hydroxylase gene 5' flanking region polymorphism-1021 C-->T with attention deficit hyperactivity disorder (ADHD) in Han children. METHODS: ADHD was diagnosed according to the DSM-IV criteria. DNA was extracted and PCR was performed to examine the DBH-1021C-->T polymorphism. HHRR was used to test the association of dopamine beta-hydroxylase gene with different subtypes of ADHD. RESULTS: HHRR results showed this polymorphism had a tendency to be associated with the inattention subtype (P=0.067) and the combined subtype (P=0.076). The T allele was the protective factor of the inattentive subtype (P=0.07), and the risk factor of the combined subtype (P=0.08). After dividing the 292 nuclear families according to sex, DBH-1021C-->T polymorphism was found to be associated with the combined subtype (P=0.04) with the T allele as the risk factor (P=0.02). There were no positive findings among the girl nuclear families of ADHD. CONCLUSION: DBH gene is related to ADHD combined subtype and inattention subtype. The genetic basis of ADHD combined subtype and is inattention is different, and is influenced by sex factor." [Abstract]

Rogeness GA, Maas JW, Javors MA, Macedo CA, Fischer C, Harris WR.
Attention deficit disorder symptoms and urine catecholamines.
Psychiatry Res 1989 Mar;27(3):241-51
"The symptoms of hyperactivity, impulsivity, and concentration deficits associated with attention deficit disorder (ADD) may be related, in part, to alterations in dopaminergic and noradrenergic functioning. In this study we correlate the above symptoms with 24-hour urinary catecholamines and their metabolites in emotionally disturbed boys divided into two groups based on their plasma dopamine-beta-hydroxylase (DBH) activities and also divided into the following diagnostic groups: conduct disorder, undersocialized; conduct disorder, socialized; and subjects without conduct disorder. Boys in the low DBH group showed significant correlations between the ADD symptoms and the biochemical measures. The low DBH group may be more genetically homogeneous with regard to catecholamine function, making relationships between catecholamine function and behavior more visible. The group of boys with conduct disorder, socialized had higher 24-hour urinary norepinephrine and vanillylmandelic acid output. The relationship between monoamines and their metabolites appeared to differ among diagnostic groups." [Abstract]

Durston S, Fossella JA, Casey BJ, Hulshoff Pol HE, Galvan A, Schnack HG, Steenhuis MP, Minderaa RB, Buitelaar JK, Kahn RS, van Engeland H
Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls.
Mol Psychiatry. 2005 Jul;10(7):678-85.
Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior. [Abstract]

Aron AR, Poldrack RA
The cognitive neuroscience of response inhibition: relevance for genetic research in attention-deficit/hyperactivity disorder.
Biol Psychiatry. 2005 Jun 1;57(11):1285-92.
Psychological functions that are behaviorally and neurally well specified may serve as endophenotypes for attention-deficit/hyperactivity disorder (ADHD) research. Such endophenotypes, which lie between genes and symptoms, may relate more directly to relevant genetic variability than does the clinical ADHD syndrome itself. Here we review evidence in favor of response inhibition as an endophenotype for ADHD research. We show that response inhibition--operationalized by Go/NoGo or Stop-signal tasks--requires the prefrontal cortex (PFC), in particular the right inferior frontal cortex (IFC); that patients with ADHD have significant response inhibition deficits and show altered functional activation and gray matter volumes in right IFC; and that a number of studies indicate that response inhibition performance is heritable. Additionally, we review evidence concerning the role of the basal ganglia in response inhibition, as well as the role of neuromodulatory systems. All things considered, a combined right IFC structure/function/response inhibition phenotype is a particularly good candidate for future heritability and association studies. Moreover, a dissection of response inhibition into more basic components such as rule maintenance, vigilance, and target detection may provide yet better targets for association with genes for neuromodulation and brain development. [Abstract]

Waldman ID
Statistical approaches to complex phenotypes: evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder.
Biol Psychiatry. 2005 Jun 1;57(11):1347-56.
There is renewed interest among psychiatric geneticists in endophenotypes, constructs posited to be more directly and strongly influenced by candidate genes than manifest disorders. Researchers have proposed various criteria for the selection of endophenotypes useful in finding genes that underlie psychiatric disorders. These criteria include the endophenotype's psychometric properties, its relationship to the disorder in the population and within families, its expression in probands' unaffected relatives, its heritability and common genetic influences with the disorder, its association with candidate genes that underlie the disorder, and its mediation and moderation of association between the candidate gene and the disorder. In this article, analytic methods for evaluating the validity and utility of putative endophenotypes consistent with these proposed criteria are reviewed. The use of such analyses is illustrated with data on childhood attention-deficit/hyperactivity disorder and time to complete Trails A and B from both a candidate gene study of clinically referred children and a study of non-referred twins. It is demonstrated that both putative endophenotypes show association with the dopamine D4 receptor gene and meet most (but not all) of the criteria proposed for their validity and utility. [Abstract]

Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z
Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP -616.
Am J Med Genet B Neuropsychiatr Genet. 2004 Nov 15;131(1):33-7.
Abnormalities of dopamine neurotransmission have been hypothesized to play an important role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Support for this has come from numerous association studies on candidate genes including the dopamine D4 receptor gene (DRD4). One of the most replicated associations between ADHD and the dopaminergic system is the 7-repeat allele of the VNTR polymorphism of this gene. A lack of association between this marker and ADHD has also been reported in several investigations. In the absence of a firm link between the number of the VNTR repeats and the function of the gene, we sought to investigate several additional markers at the 5'-end of the gene with potential influence on the expression of the DRD4. We observed a significant over transmission of single nucleotide polymorphism (SNP) (chi(2) = 7.45, P = 0.008, OR = 1.63). In addition, an excess transmission of the A allele of the -521 SNP was observed, although it did not attain statistical significance (chi(2) = 2.14, P = 0.17, OR = 1.25). Linkage disequilibrium (LD) analysis demonstrated a weak level of D' between any of the tested markers implying that this may be a region of high recombination. It also raises the possibility that the new association with ADHD may be independent of the 7-repeat allele. Further analyses, preferably in samples demonstrating association with the VNTR, or in other ethnic groups, are required to confirm these observations. [Abstract]

El-Faddagh M, Laucht M, Maras A, Vohringer L, Schmidt MH.
Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: a longitudinal study from birth to 11 years of age.
J Neural Transm. 2004 Jul;111(7):883-9. Epub 2004 Feb 04.
"Background: In recent years, a growing number of studies has focused on the dopamine D4 receptor gene (DRD4) as mediating the susceptibility to attention-deficit/hyperactivity disorder (ADHD). While their results are contradictory, the reason for this inconsistency remains as yet unclear. Method: The present study sought to examine the association between ADHD and the DRD4 exon III polymorphism during child development using longitudinal data from a high-risk community sample (n=265, 129 females, 126 males) who have been followed from birth to 11 years of age. Results: Higher rates of ADHD were observed in boys with the 7 repeat allele of exon III than in boys with other alleles at the ages of 4 1/2 (Fisher's exact test, p=.061), 8 (p=.026), and 11 years (p=.005). Boys with this allele also exhibited higher rates of persistent disorder (p=.024). In girls, a trend towards an association (p=.055) with the 7 repeat allele emerged only at preschool age. Conclusions: These findings provide additional evidence for the role of the dopamine D4 receptor in ADHD during the course of child development." [Abstract]

Langley K, Marshall L, Van Den Bree M, Thomas H, Owen M, O'Donovan M, Thapar A.
Association of the dopamine d(4) receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD.
Am J Psychiatry. 2004 Jan; 161(1): 133-8.
"OBJECTIVE: Association between attention deficit hyperactivity disorder (ADHD) and the 7-repeat allele of a variant (a 48bp variable number of tandem repeats) in the dopamine D(4) receptor gene (DRD4) has been widely documented. A meta-analysis of 21 studies revealed evidence of significant association. In this article the authors examine whether the DRD4 7-repeat allele is associated with performance on a variety of neuropsychological tasks in children with ADHD. METHOD: The presence or absence of the 7-repeat allele was determined in 133 drug-naive children 6 to 13 years of age who fulfilled diagnostic criteria for ADHD. These children were then assessed on several neuropsychological tests known to be associated with attention, impulse control, and response inhibition (the Continuous Performance Test, Matching Familiar Figures Test, Go/No Go Task, and Stop Task). Activity levels were assessed with an actigraph. Children with and without at least one 7-repeat allele were compared with each other and with children in a previous population-based study. RESULTS: Children who had the 7-repeat allele had significantly more incorrect responses on the Matching Familiar Figures Test (16.1 versus 14.3) than children who did not have the allele. Children with the allele also had shorter mean reaction times for incorrect responses on the Matching Familiar Figures Test (846.1 versus 1103.7 msec) and on the Stop Task (116.6 versus 134.1 msec) than children without the allele. Children with the allele also displayed higher activity levels. The children with and without the allele did not differ significantly in number of ADHD symptoms when the symptoms were split into the areas of inattention and hyperactivity/impulsivity. Both groups of children with ADHD were more neuropsychologically impaired than the nonpatient comparison group. CONCLUSIONS: In children with ADHD, possession of the DRD4 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by ADHD symptom severity." [Abstract]

James Swanson, Jaap Oosterlaan, Michael Murias, Sabrina Schuck, Pamela Flodman, M. Anne Spence, Michael Wasdell, Yuanchun Ding, Han-Chang Chi, Moyra Smith, Miranda Mann, Caryn Carlson, James L. Kennedy, Joseph A. Sergeant, Patrick Leung, Ya-Ping Zhang, Avi Sadeh, Chuansheng Chen, Carol K. Whalen, Kimberley A. Babb, Robert Moyzis, and Michael I. Posner
Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention
PNAS 97: 4754-4759; published online before print as 10.1073/pnas.080070897
"An association of the dopamine receptor D4 (DRD4) gene located on chromosome 11p15.5 and attention deficit/hyperactivity disorder (ADHD) has been demonstrated and replicated by multiple investigators. A specific allele [the 7-repeat of a 48-bp variable number of tandem repeats (VNTR) in exon 3] has been proposed as an etiological factor in attentional deficits manifested in some children diagnosed with this disorder. In the current study, we evaluated ADHD subgroups defined by the presence or absence of the 7-repeat allele of the DRD4 gene, using neuropsychological tests with reaction time measures designed to probe attentional networks with neuroanatomical foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7-present subgroup showed normal speed and variability of response whereas the average reaction times of the 7-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7-present subgroup seemed to be free of some of the neuropsychological abnormalities thought to characterize ADHD.
...
This study indicates that the 7-present genotype is not a necessary condition for the manifestation of cognitive abnormalities thought to be characteristic of children with DSM-IV diagnoses of ADHD-combined type. Although the 7-absent subgroup shows clear abnormalities in performance on these neuropsychological tests of attention, the 7-present subgroup was free of critical neuropsychological abnormalities thought to characterize children with psychiatric (DSM-IV) diagnoses of ADHD. This suggests that the 7-repeat allele may identify a subgroup with the behavioral but not the cognitive components of ADHD." [Full Text]

Manor I, Tyano S, Eisenberg J, Bachner-Melman R, Kotler M, Ebstein RP.
The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA).
Mol Psychiatry 2002;7(7):790-4
"One particular candidate gene, the dopamine D4 receptor (DRD4), has been the focus of intense study regarding ADHD since the original investigation by La Hoste et al, an observation confirmed by a recent metaanalysis. However, two previous studies from Israel failed to observe this association. We have now recruited an additional sample and, overall, in the combined sample of 178 triads we observe using the transmission disequilibrium test, preferential transmission of the short allele. Additionally, we now report the effect of the DRD4 repeat region on the Test Of Variables of Attention (TOVA), a widely used computerized continuous performance test. Probands with the short exon III repeat performed significantly worse on the TOVA measured both by errors of commission and response time variable. Intriguingly, a 'dose effect' was observed. Increasing repeat size is accompanied by a reduced number of errors of commission and a significant difference is observed between the 2 vs 7 repeats. On the whole, our results lend credence to the notion that the relationship between the DRD4 receptor and ADHD is complex and may be reflecting linkage disequilibrium between the 7 or long DRD4 exon III repeats and a 'true' risk allele in this gene or a neighboring locus." [Abstract]

Bellgrove MA, Hawi Z, Lowe N, Kirley A, Robertson IH, Gill M
DRD4 gene variants and sustained attention in attention deficit hyperactivity disorder (ADHD): effects of associated alleles at the VNTR and -521 SNP.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jul 5;136(1):81-6.
Associations between attention deficit hyperactivity disorder (ADHD) and genetic variants within the dopamine D4 receptor gene have been much reported. Variants investigated include the 7-repeat allele of a VNTR within the third exon, and two SNPs (-521 and -616) located with the promoter region. We investigated the relationship between the VNTR, -521, and -616 SNPs and sustained attention performance in 54 ADHD probands, relative to a non-genotyped control group. Participants performed the Sustained Attention to Response Task (SART) in which the response to an unpredictably occurring target digit must be inhibited. This task, therefore, challenged sustained attention and included a response inhibition component. Consistent with previous reports, ADHD participants possessing the 7-repeat allele of the VNTR outperformed those children not possessing this allele, both in terms of errors and response variability. In family based analyses, better performance on the SART tended to predict biased transmission of the 7-repeat allele from heterozygous parents. For the -521 SNP, A allele homozygotes showed greater impairment than heterozygotes or those not possessing this allele, both in terms of total errors and response variability. Family based analysis showed that higher total errors on the SART predicted transmission of the A allele from heterozygous parents. There were no effects of the -616 SNP. Our results suggest dissociable effects of the "associated alleles" of DRD4 gene variants on sustained attention: while the 7-repeat allele of the VNTR is associated with relatively better performance, the A allele of the -521 SNP is associated with poorer performance. [Abstract]

Grady DL, Harxhi A, Smith M, Flodman P, Spence MA, Swanson JM, Moyzis RK
Sequence variants of the DRD4 gene in autism: further evidence that rare DRD4 7R haplotypes are ADHD specific.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jul 5;136(1):33-5.
A high prevalence of rare dopamine receptor D4 (DRD4) alleles in children diagnosed with attention-deficit hyperactivity disorder (ADHD) has been reported [Grady et al., 2003]. In this prior study, extensive resequencing/haplotype data of the DRD4 locus was used to suggest that population stratification was not the explanation for the high prevalence of rare alleles. In the current study, DNA resequencing/haplotyping was conducted on 136 DRD4 alleles obtained from autism probands, collected from the same geographic population as the prior ADHD probands (Orange County, CA). A number of studies have suggested that the susceptibility genes underlying these two disorders might partially overlap. Rare DRD4 variants were not uncovered in this autism sample beyond that expected by chance. These results suggest strongly that the high prevalence of rare DRD4 alleles in ADHD probands is due to ascertainment of the sample by diagnosis of ADHD. [Abstract]

Swanson JM, Sunohara GA, Kennedy JL, Regino R, Fineberg E, Wigal T, Lerner M, Williams L, LaHoste GJ, Wigal S.
Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach.
Mol Psychiatry 1998 Jan;3(1):38-41
"Previously in this journal, we reported an association of the dopamine D4 receptor gene (DRD4) and attention deficit hyperactivity disorder (ADHD). In a population-association (case-control) study of 39 children with a refined phenotype of ADHD and 39 ethnically matched controls, we observed an increased percentage of the 7 repeat allele (29% vs 12%) and the 7+ genotype (49% vs 21%) in the ADHD group compared to the control group. In a replication and an extension of our initial study, we recruited another sample of ADHD subjects and found percentages of the 7 repeat allele (28%) and the 7+ genotype (48%) consistent with our previous findings. We used a family-based approach to evaluate a predicted association of DRD4 and ADHD based on a test of allele transmission focused on the 7 repeat allele. We identified 52 families based on the diagnosis of the refined phenotype of ADHD in the proband and the availability of DNA from both biological parents as well as the proband. Haplotype relative risk (HRR) analysis was performed to test our a priori hypothesis and produced significant results (chi-square = 4.65, P < 0.035). This provides additional evidence that the DRD4 gene is associated with a refined phenotype of ADHD." [Abstract]

Grady DL, Chi HC, Ding YC, Smith M, Wang E, Schuck S, Flodman P, Spence MA, Swanson JM, Moyzis RK.
High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder.
Mol Psychiatry. 2003 May;8(5):536-45.
"Associations have been reported of the 7-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD." [Abstract]

Lynn DE, Lubke G, Yang M, McCracken JT, McGough JJ, Ishii J, Loo SK, Nelson SF, Smalley SL
Temperament and character profiles and the dopamine D4 receptor gene in ADHD.
Am J Psychiatry. 2005 May;162(5):906-13.
OBJECTIVE: This study was designed to investigate the link among attention deficit hyperactivity disorder (ADHD) in adults, novelty-seeking temperament, and the 48-base pair (bp) dopamine D4 receptor (DRD4) gene variant. METHOD: This study drew from a larger molecular genetic study of ADHD in which the ascertainment criterion was having an affected sibling pair with ADHD. Parents (N=171) from 96 families provided data. Of the 171 parents, 56 (33%) had a lifetime history of ADHD, with 28 (50%) continuing to meet DSM-IV criteria (i.e., "persistent" ADHD). Latent variable modeling was used to test whether the DRD4 gene variant or Temperament and Character Inventory factors could predict ADHD. RESULTS: Using latent variable modeling, the authors were able to confirm the first-order factor structure of the Temperament and Character Inventory. Furthermore, novelty seeking predicted ADHD lifetime diagnosis (R(2)=26%), while the DRD4 gene variant independently predicted ADHD (R(2)=5%) but not novelty seeking. CONCLUSIONS: In this unique sample of parents from multiply affected ADHD families, novelty seeking and the 48-bp DRD4 variant were associated with a lifetime history of ADHD. However, the association between novelty seeking and ADHD does not appear to be due to variation in the 48-bp DRD4 variant. [Abstract]

Mill J, Fisher N, Curran S, Richards S, Taylor E, Asherson P.
Polymorphisms in the dopamine D4 receptor gene and attention-deficit hyperactivity disorder.
Neuroreport. 2003 Aug 6;14(11):1463-6.
"SUMMARY: There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A 48 bp repeat in exon three of the dopamine D4 receptor gene has been widely studied in clinical ADHD samples, and a meta-analysis of published studies suggests it is associated with ADHD. A number of other polymorphisms across this gene have been characterised but not so thoroughly investigated in relation to ADHD. In this study we have genotyped five polymorphisms (a 120 bp promoter-region duplication, the -616 C/G substitution, the -521 C/T substitution, a poly-G repeat in intron 1, and the 48 bp exon 3 repeat) across the gene in a large clinical sample (n = 188) and their families. We found that none of the markers is individually associated with ADHD, although there is evidence to suggest that a haplotype of markers in the 5' promoter region of the gene (allele 2 of the 120 bp duplication, the C allele of the -616 substitution, and the C allele of the -521 substitution) may confer susceptibility." [Abstract]

LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL.
Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder.
Mol Psychiatry 1996 May;1(2):121-4 [Abstract]

Levitan RD, Masellis M, Lam RW, Muglia P, Basile VS, Jain U, Kaplan AS, Tharmalingam S, Kennedy SH, Kennedy JL.
Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder.
Neuropsychopharmacology. 2004 Jan;29(1):179-86.
"There is significant evidence that altered dopamine activity plays a role in seasonal affective disorder (SAD). The current study examined three separate genetic hypotheses for SAD related to the 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), a variant associated with decreased affinity for dopamine. We examined the possible contribution of 7R to the overall expression of SAD, attention deficit disorder (ADD) comorbidity, and body weight regulation. As part of an ongoing genetic study of increased eating behavior and mood in female subjects, 108 women with winter SAD and carbohydrate craving/weight gain were administered the Wender-Utah Rating Scale to measure childhood ADD symptomatology, and a questionnaire to assess maximal lifetime body mass index (BMI). To test for an association between 7R and the categorical diagnosis of SAD, the transmission disequilibrium test (TDT) was used in a subsample of probands providing familial DNA. Standard parametric tests were used to compare childhood ADD symptoms and maximal lifetime BMI across the two genotypic groups defined by the presence or absence of 7R. The TDT found no initial evidence for an association between 7R and the categorical diagnosis of SAD. However, 7R carriers reported significantly greater inattention and dysphoria in childhood (p=0.01 and 0.001, respectively) and a higher maximal lifetime BMI (p=0.007) than did probands without this allele. Furthermore, excluding probands with extreme obesity (maximal BMI >40), a strong correlation was found linking childhood inattentive symptoms and maximal lifetime BMI (r=0.35, p=0.001). In overeating women with SAD, the 7R allele of DRD4 may be associated with a unique developmental trajectory characterized by attentional deficits and dysphoria in childhood and mild to moderate obesity in adulthood. This developmental course may reflect different manifestations of the same underlying vulnerability related to central dopamine dysfunction. Given the possibility of population stratification when studying genotype/phenotype relationships, future use of genomic controls and replication of our findings in other overeating and/or ADD populations are needed to confirm these initial results." [Abstract]

Curran S, Mill J, Sham P, Rijsdijk F, Marusic K, Taylor E, Asherson P.
QTL association analysis of the DRD4 exon 3 VNTR polymorphism in a population sample of children screened with a parent rating scale for ADHD symptoms.
Am J Med Genet 2001 May 8;105(4):387-93
"Current developments in molecular genetics have led to a rapid increase in research aimed at the identification of genetic variation that influences complex human phenotypes. One phenotype that has aroused a great deal of interest is the behavioral trait hyperactivity and the related clinical disorder attention-deficit hyperactivity disorder (ADHD). The driving force behind the molecular genetic research in this area is the overwhelming evidence from quantitative genetic studies that show high heritablility (h(2) = 0.7-0.9) for the behaviors characterizing the diagnosis of ADHD, whether the disorder is viewed as a categorical entity or a continuous trait. To date, molecular studies have aimed at identifying susceptibility genes for ADHD, defined using operational diagnostic criteria, and have focused on variation within genes that regulate dopamine neurotransmission. Several studies report ADHD to be associated with the 7-repeat allele of a 48 bp repeat polymorphism (DRD4-7) in exon 3 of the dopamine D4 receptor gene (DRD4). In this study, we take a dimensional perspective of ADHD and examine the relationship of this DRD4 polymorphism in a sample of children selected from the general population on the basis of high and low scores on the five ADHD items of the Strengths and Difficulties Questionnaire (SDQ) as rated by their parents. We found a significant relationship between DRD4-7 and high-scoring individuals [chi-square = 8.63; P = 0.003; OR = 2.09 (95% CI 1.24 < OR < 3.54), F-statistic = 7.245; P = 0.008]." [Abstract]

Muglia P, Jain U, Macciardi F, Kennedy JL.
Adult attention deficit hyperactivity disorder and the dopamine D4 receptor gene.
Am J Med Genet 2000 Jun 12;96(3):273-7
"Attention deficit hyperactivity disorder (ADHD) is a prevalent psychiatric condition in children and follow up studies have indicated that 22-33% of patients continue to suffer from ADHD during late adolescence and adulthood. Convincing evidence supports the contribution of genetic factors in the etiology of ADHD, and the interaction of the psychostimulants with the dopamine system suggests that dopamine is involved in the pathophysiology. The 7-repeat allele of the 48 base pair repeat of the dopamine D4 receptor gene (DRD4) has been reported, with several replications, to be associated with ADHD in children. We tested for the presence of association between the DRD4 48 base repeat and adult ADHD in two independent samples: one comprised of cases and ethnically matched controls, and the second made up of nuclear families. Each case was assessed using a battery of adult ADHD assessment instruments. The analysis of the 66 cases and 66 controls showed a significantly higher presence of the 7-repeat in the adult ADHD patients vs. controls (chi(2) = 5.65; df = 1; P = 0.01). In the analysis of transmission of DRD4 alleles in 44 nuclear families with the transmission disequilibrium test, a trend was observed toward a increased transmission of the 7-repeat from the heterozygous parents to the affected offspring (chi(2) = 2.00; df = 1; P = 0.15). When the two samples were combined, the overall significance was stronger (N = 110; z = 2.68; P = 0.003). The results of our study suggest a role of the 7-repeat allele in adult subjects suffering from ADHD. This finding is an important continuation of the group of studies that together strongly suggest the involvement of DRD4 in ADHD." [Abstract]

El-Faddagh M, Laucht M, Maras A, Vöhringer L, Schmidt MH
Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: a longitudinal study from birth to 11 years of age.
J Neural Transm. 2004 Jul;111(7):883-9.
BACKGROUND: In recent years, a growing number of studies has focused on the dopamine D4 receptor gene (DRD4) as mediating the susceptibility to attention-deficit/hyperactivity disorder (ADHD). While their results are contradictory, the reason for this inconsistency remains as yet unclear. METHOD: The present study sought to examine the association between ADHD and the DRD4 exon III polymorphism during child development using longitudinal data from a high-risk community sample (n = 265, 129 females, 126 males) who have been followed from birth to 11 years of age. RESULTS: Higher rates of ADHD were observed in boys with the 7 repeat allele of exon III than in boys with other alleles at the ages of 4 1/2 (Fisher's exact test, p = .061), 8 (p = .026), and 11 years (p = .005). Boys with this allele also exhibited higher rates of persistent disorder (p = .024). In girls, a trend towards an association (p = .055) with the 7 repeat allele emerged only at preschool age. CONCLUSIONS: These findings provide additional evidence for the role of the dopamine D4 receptor in ADHD during the course of child development. [Abstract]

Arcos-Burgos M, Castellanos FX, Konecki D, Lopera F, Pineda D, Palacio JD, Rapoport JL, Berg K, Bailey-Wilson J, Muenke M.
Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate.
Mol Psychiatry. 2004 Mar;9(3):252-9.
"Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attention-deficit/hyperactivity disorder (ADHD) has been suggested by case-control- and nuclear-family-based studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele." [Abstract]

Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK.
The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus.
Am J Hum Genet. 2004 May;74(5):931-44. Epub 2004 Apr 09. [Abstract]

ASHERSON, PHILIP J., CURRAN, SARAH
Approaches to gene mapping in complex disorders and their application in child psychiatry and psychology
Br J Psychiatry 2001 179: 122-128
"BACKGROUND: Twin studies demonstrate the importance of genes and environment in the aetiology of childhood psychiatric and neurodevelopmental disorders. Advances in molecular genetics enable the identification of genes involved in complex disorders and enable the study of molecular mechanisms and gene--environment interactions. AIMS: To review the role of molecular genetics studies in childhood behavioural and developmental traits. METHOD: Molecular approaches to complex disorders are reviewed, with examples from autism, reading disability and attention-deficit hyperactivity disorder (ADHD). RESULTS: The most robust finding in ADHD is the association of a variable number tandem repeat polymorphism in exon 3 of the DRD4 gene. Other replicated associations with ADHD are outlined in the text. In autism, there is a replicated linkage finding on chromosome 7. Linkage studies in reading disability have confirmed a locus on chromosome 6 and strongly suggest one on chromosome 15. CONCLUSIONS: In the next 5--0 years susceptibility genes for these disorders will be established. Describing their relationship to biological and behavioural function will be a far greater challenge." [Full Text]

Payton A, Holmes J, Barrett JH, Sham P, Harrington R, McGuffin P, Owen M, Ollier W, Worthington J, Thapar A.
Susceptibility genes for a trait measure of attention deficit hyperactivity disorder: a pilot study in a non-clinical sample of twins.
Psychiatry Res 2001 Dec 31;105(3):273-8
"Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, and molecular genetic studies are underway, with most researchers focusing on identifying susceptibility genes in clinical samples with ADHD. An alternative approach is to search for quantitative trait loci underlying the trait measure of ADHD in non-clinical samples. Positive findings of association of the dopamine transporter DAT1 480 bp allele (allele 10) and the DRD4 7 repeat allele with clinical ADHD have been previously reported. In this pilot study, we examined these polymorphisms in a selected population-based sample of twins (50 high scoring pairs, 42 low scoring pairs). There was a trend for an increase in the frequency of the dopamine receptor DRD4 7 repeat allele in the high-scoring concordant monozygotic twins (odds ratio=1.4). Although this result was not statistically significant, the frequency of the 7 repeat allele was similar to that reported for our clinic sample of ADHD patients drawn from the same geographical area. There was a non-significant trend for an increased frequency of the DAT1 allele 10 (odds ratio=1.3). These results suggest that a molecular genetic study based on a questionnaire-derived measure of ADHD in a non-clinical sample is feasible and the results appear to be comparable with those from studies of clinical cases. However, sample size and power are key issues to consider when using this approach." [Abstract]

Sunohara GA, Roberts W, Malone M, Schachar RJ, Tannock R, Basile VS, Wigal T, Wigal SB, Schuck S, Moriarty J, Swanson JM, Kennedy JL, Barr CL.
Linkage of the dopamine D4 receptor gene and attention-deficit/hyperactivity disorder.
J Am Acad Child Adolesc Psychiatry 2000 Dec;39(12):1537-42
"OBJECTIVE: There is considerable evidence supporting a genetic component in the etiology of attention-deficit/hyperactivity disorder (ADHD). Because stimulant medications act primarily on the dopaminergic system, dopamine system genes are prime candidates for genetic susceptibility factors for ADHD. Previous studies by several groups have observed a significant association of ADHD and an allele with 7 copies of the 48 base pair repeat in the third exon of the dopamine D4 receptor. METHOD: The authors sought to replicate these previous findings by collecting an independent sample of families from Toronto, Ontario, Canada, and confirming this finding in an expanded sample of ADHD families collected from Irvine, California. Using the transmission disequilibrium test (TDT), the authors tested for biased transmission of the 7-repeat allele at the exon III polymorphism of the dopamine D4 receptor locus in these samples of ADHD subjects. RESULTS: Biased transmission of the 7-repeat allele from parents to ADHD probands and their affected siblings was observed in the 2 new samples of families collected in Toronto and Irvine (TDT chi2 = 2.711, 1 df, one-sided p value = .050) and for these samples combined with the 52 families previously reported from Irvine (TDT chi2 = 6.426, 1 df, one-sided p value = .006). CONCLUSIONS: The results of this study further support the possibility of a role of the dopamine D4 receptor locus in ADHD." [Abstract]

Hawi Z, McCarron M, Kirley A, Daly G, Fitzgerald M, Gill M.
No association of the dopamine DRD4 receptor (DRD4) gene polymorphism with attention deficit hyperactivity disorder (ADHD) in the Irish population.
Am J Med Genet 2000 Jun 12;96(3):268-72
"Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset syndromes affecting 3%-6% of school-age children worldwide. Although the biological basis of ADHD is unknown, a dopaminergic abnormality has long been suggested. The dopamine D4 receptor gene (DRD4) has been mapped to chromosome 11p15.5 and has been implicated in predisposition to ADHD. Several independent genetic association studies have demonstrated increased frequency of the DRD4 7-repeat allele in ADHD cases compared with controls or excess transmission of the 7-repeat allele from parents to affected offspring. However, there have also been few negative studies. In this study we investigated 78 ADHD parent proband trios and 21 parent proband pairs for the transmission of the DRD4 alleles in HHRR and case control design. We found no significant differences in the frequency of the DRD4 alleles transmitted or not transmitted to ADHD cases from their parents nor when comparing case allele frequencies to ethnically matched controls. Therefore, it is unlikely that the DRD4 7-repeat allele is associated with ADHD in the Irish population." [Abstract]

Holmes J, Payton A, Barrett JH, Hever T, Fitzpatrick H, Trumper AL, Harrington R, McGuffin P, Owen M, Ollier W, Worthington J, Thapar A.
A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder.
Mol Psychiatry 2000 Sep;5(5):523-30
"Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition of early childhood onset characterised by marked inattention, hyperactivity and impulsiveness. Molecular genetic investigations of ADHD have found positive associations with the 480-bp allele of a VNTR situated in the 3' untranslated region of DAT1 and allele 7 of a VNTR in exon 3 of DRD4. A number of independent studies have attempted to replicate these findings but the results have been inconsistent. We used both family-based and case control approaches to examine these polymorphisms in a sample of 137 children diagnosed with ICD-10, DSM-IV or DSM-III-R ADHD. We found no evidence of association with the DAT1 polymorphism, despite a sample size that has up to 80% power to detect a previously reported effect size. We observed a significant increase in the DRD4 7 repeat allele amongst ADHD probands (21.7%) and their parents (18.9% in mothers, 22.3% in fathers), compared to ethnically matched controls (12.8%). However TDT analysis showed no preferential transmission of allele 7 to ADHD probands." [Abstract]

Kirley A, Lowe N, Mullins C, McCarron M, Daly G, Waldman I, Fitzgerald M, Gill M, Hawi Z
Phenotype studies of the DRD4 gene polymorphisms in ADHD: association with oppositional defiant disorder and positive family history.
Am J Med Genet B Neuropsychiatr Genet. 2004 Nov 15;131(1):38-42.
The objective of this study was to investigate association of DRD4 polymorphisms with ADHD subtypes for which there is evidence for increased heritability. The genetic variants tested were the 120 bp insertion/deletion, the -616, -521, -376, and the 48 bp DRD4 VNTR. The primary analyses were of association with oppositional defiant disorder (ODD), conduct disorder (CD), and diagnostic subtypes. Secondary analyses of clinical subtype were exploratory in nature and included analysis of association of DRD4 polymorphisms with family history of ADHD. We observed significant association between DRD4 7-repeat allele transmission and ADHD children with comorbid ODD (chi(2) = 6.74, df = 1, P = 0.01, OR = 2.45) The DRD4 7-repeat allele was also significantly associated with family history positive ADHD (chi(2) = 10.12, df = 1, P = 0.0021, OR = 3.57). We observed no significant distortion in the transmission of any of the tested DRD4 variants with inattentive or hyperactive-impulsive subtypes or symptom dimensions. In conclusion, our findings of increased DRD4 7-repeat allele transmission in ODD extend those reported by Holmes et al. To our knowledge, this is the first study to report association of the DRD4 7-repeat allele with ADHD children who have a positive family history of ADHD. Overall, the results from this study support the investigation of clinical subtypes in molecular genetic studies of ADHD. [Abstract]

Qian Q, Wang Y, Li J, Yang L, Wang B, Zhou R.
[Association studies of dopamine D4 receptor gene and dopamine transporter gene polymorphisms in Han Chinese patients with attention deficit hyperactivity disorder]
Beijing Da Xue Xue Bao. 2003 Aug;35(4):412-8.
"OBJECTIVE: To investigate association of the 48 bp variable number of tandem repeat (VNTR) polymorphism in the D4 receptor gene (DRD4) exon 3 and 40 bp VNTR polymorphism in the dopamine transporter gene (DAT1) 3' untranslated region with attention deficit hyperactivity disorder (ADHD) in Han Chinese children. METHODS: The study samples were comprised of 340 ADHD children, 226 unrelated controls and 202 integrated ADHD trios (included proband and biological parents). The polymorphisms consisted of 48 bp VNTR in exon 3 of DRD4, and 40 bp VNTR in the 3' untranslated region of DAT1. Associations of polymorphisms with ADHD and its subtypes were examined by: (i) comparing cases and controls; and (ii) using family-based association study in an extension of exact transmission-disequilibrium test (ETDT) and haplotype-based haplotype relative risk (HHRR). RESULTS: The repeat numbers at the DRD4 48 bp locus ranged from 2-6 repeats in the Han Chinese controls, with the most common being the 4-repeat (77%) and 2-repeat (19.4%) alleles. Neither the 7-repeat allele nor longer repeats were found. For the DAT1, the repeat numbers at the 40 bp locus ranged from 6-7 repeats and 9-11 repeats. The 10-repeat allele was the most frequent (90.7%). The long-repeat alleles of DRD4 (ranging from 4-6 repeats) and DAT1 (ranging from 11-12 repeats), were present more frequently in ADHD probands than in controls. Our primary analyses failed to replicate the associations between ADHD and 7-repeat allele of DRD4 and the 10-repeat allele of DAT1. CONCLUSION: The long-repeat alleles of DRD4 (after a stratification by gender) and DAT1 may increase the risk for ADHD in Han Chinese children." [Abstract]

Leung PW, Lee CC, Hung SF, Ho TP, Tang CP, Kwong SL, Leung SY, Yuen ST, Lieh-Mak F, Oosterlaan J, Grady D, Harxhi A, Ding YC, Chi HC, Flodman P, Schuck S, Spence MA, Moyzis R, Swanson J
Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele.
Am J Med Genet B Neuropsychiatr Genet. 2005 Feb 5;133(1):54-6.
There is an increased prevalence of the 7-repeat (7R) allele of the dopamine receptor D4 (DRD4) gene in attention-deficit/hyperactivity disorder (ADHD). However, the population prevalence of the 7R allele varies considerably across ethnicity and is very low in Asians. To test whether this 7R allele/ADHD association still held in a Chinese clinical sample, 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate-responders were genotyped. None of them had a DRD4 7R allele. Instead, we observed a significantly increased prevalence of the 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically-matched controls (20%) (chi(2)(1d.f.) = 5.90, P = 0.015). This approximately 1.65-fold increase of the 2R allele in our probands is close to the observed increase of the 7R allele in European-ancestry ADHD children. Recent genetic studies have indicated that the 2R allele in Asians is likely derived from the 7R allele. Further, available biochemical data indicate that both the 2R and 7R protein have blunted responses to dopamine compared to the 4R protein. Based on these results, we propose that the observed increased prevalence of the 2R allele in our Han Chinese ADHD probands is still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Recent studies have suggested that any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesize that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD that holds across ethnicity. The present findings, however, obtained with a small ADHD sample size, should be replicated. [Abstract]

Maher BS, Marazita ML, Ferrell RE, Vanyukov MM.
Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis.
Psychiatr Genet 2002 Dec;12(4):207-15
"The dopamine system may play a major role in the development of attention deficit hyperactivity disorder (ADHD). We applied a random-effects model meta-analysis to family-based studies of association between ADHD and the dopamine system genes DRD4, DRD5 and DAT1. A statistical test of heterogeneity was conducted for each group of studies. The meta-analysis of DRD4 included data from 13 studies, with a total of 571 informative meioses. The pooled odds ratio estimate was 1.41 (95% CI 1.20-1.64, =1.57x10 ), demonstrating positive association. For DRD5, data from five studies, with a total of 340 informative meioses, were combined yielding a pooled odds ratio of 1.57 (95% CI 1.25-1.96, =8.28x10 ). Eleven studies examining DAT1, with a total of 824 informative meioses, yielded a non-significant pooled odds ratio estimate of 1.27 (95% CI 0.99-1.63, 0.06). There was no support of heterogeneity between the studies. Overall, the meta-analyses support the involvement of the dopamine system genes in ADHD liability variation and suggest the need for studies examining interactions between these genes." [Abstract]

Manor I, Tyano S, Mel E, Eisenberg J, Bachner-Melman R, Kotler M, Ebstein RP.
Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA).
Mol Psychiatry 2002;7(6):626-32
"Monoamine oxidase A (MAO A) is located on the X chromosome and metabolizes biogenic amines including dopamine, norepinephrine and serotonin. A functional promoter-region polymorphism of this gene has been described that has been studied in a number of mental illnesses but not in attention deficit hyperactivity disorder (ADHD). In the current study, we examined the MAO A promoter-region polymorphism initially in 133 triads and observed preferential transmission of the long alleles from 74 heterozygote mothers to ADHD probands (chi(2) = 4.37, P = 0.036, df = 1). We also examined the role of this polymorphism in a computerized continuous performance test, the TOVA. Significant differences were observed on errors of commission (chi(2) = 7.021, P = 0.008) and patients carrying the long MAO A allele made significantly more such errors. Errors of commission are a measure of impulsivity. However, following Ritalin (methylphenidate) administration the association between this polymorphism and errors of commission was markedly attenuated and no longer significant at the P < 0.05 level. We also analyzed the provisional association by the case-control design. A significant difference in allele frequency was observed between 110 male probands vs 202 male controls (Pearson chi(2) = 7.94, P = 0.047). Similarly results were obtained when 19 female probands were compared to female controls (genotype chi(2) = 21.28; P = 0.0032, 3 df and allele chi(2) = 30.88, P= 0.0007, 2 df). All three complementary approaches employed (family-based, case-control and quantitative trait design) suggest a role for the MAO A promoter-region polymorphism in conferring risk for ADHD in our patient population." [Abstract]

Domschke K, Sheehan K, Lowe N, Kirley A, Mullins C, O'sullivan R, Freitag C, Becker T, Conroy J, Fitzgerald M, Gill M, Hawi Z
Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: preferential transmission of the MAO-A 941G allele to affected children.
Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):110-4.
Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Monoamine oxidases A and B (MAO-A and MAO-B) degrade biogenic amines such as dopamine and serotonin and thereby control the levels of these neurotransmitters in the central nervous system. We examined four polymorphisms in the MAO-A gene (30 bp promoter VNTR, CA microsatellite in intron 2, 941G/T SNP in exon 8, and A/G SNP in intron 12) as well as two markers in the MAO-B gene (CA microsatellite in intron 2 and T/C SNP in intron 13) for association with ADHD in an Irish sample of 179 nuclear families. TDT analysis of the examined MAO-A markers revealed a significant association of the more active MAO-A 941G allele with the disorder (chi2 = 5.1, P = 0.03, OR = 1.7). In addition, haplotype analysis revealed a significantly increased transmission of a haplotype consisting of the shorter allele of the promoter VNTR (allele 1), the 6-repeat allele of the CA microsatellite and the G-allele of the 941G/T SNP (famhap global statistic 34.54, P = 0.01) to ADHD cases. No significant distortion in the number of transmitted alleles was observed between the two examined MAO-B polymorphisms and ADHD. These findings suggest the importance of the 941G/T MAO-A polymorphism in the development of ADHD at least in the Irish population. [Abstract]

Jiang S, Xin R, Lin S, Qian Y, Tang G, Wang D, Wu X.
Linkage studies between attention-deficit hyperactivity disorder and the monoamine oxidase genes.
Am J Med Genet 2001 Dec 8;105(8):783-8
"Attention-deficit hyperactivity disorder (ADHD) is a prevalent behavioral disorder in children and the etiology of this disorder is not clear. Molecular genetic and pharmacological studies suggest the involvement of dopaminergic and noradrenergic neurotransmitter systems in ADHD, e.g., several reports have found association between ADHD and the dopamine receptor gene DRD-4, the dopamine transporter gene DAT1, and the catecholamine clearance enzyme catechol-O-methyltransferase. Monoamine oxidase (MAO) A and B genes encode enzymes that participate in the metabolism of neurotransmitters of the dopaminergic and noradrenergic systems. MAO inhibitors have been shown to be effective in the treatment of ADHD. Our previous studies showed an association between ADHD and the DXS7 locus, which is located in close vicinity to the MAO genes on chromosome X. These findings suggest that there might be linkage between ADHD and MAO genes. To test this hypothesis, we used the transmission/disequilibrium test (TDT) to test for linkage between a VNTR polymorphism at the MAOA(CA)(n) or MAOB(GT)(n) locus and DSM-III-R-diagnosed ADHD in 82 nuclear families of the Chinese population. The TDT analysis revealed linkage between ADHD and the MAOA(CA)(n) locus (chi-square = 15.25, df = 7, P < 0.05), but not the MAOB(GT)(n) locus (chi-square = 11.18, df = 7, P > 0.05). The data showed that ADHD was in linkage with the MAOA gene and suggested that MAOA might be a susceptibility factor for ADHD." [Abstract]

Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL, Cleveland HH, Sanders ML, Gard JM, Stever C.
Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity.
Am J Hum Genet 1998 Dec;63(6):1767-76
"Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children." [Abstract] [Full Text]

Mill J, Asherson P, Browes C, D'Souza U, Craig I.
Expression of the dopamine transporter gene is regulated by the 3' UTR VNTR: Evidence from brain and lymphocytes using quantitative RT-PCR.
Am J Med Genet 2002 Dec 8;114(8):975-9
"Genetic association studies provide considerable evidence that the 10-repeat allele of a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'-UTR) of the dopamine transporter gene (DAT1) is associated with a range of psychiatric phenotypes, most notably, attention deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study, we measured DAT1 messenger RNA levels in cerebellum, temporal lobe, and lymphocytes using quantitative real-time reverse-transcription polymerase chain reaction. Relative to a set of four control housekeeping genes (beta-actin, GAPD, ribosomal 18S, and beta2-microglobulin) we observed that increased levels of DAT1 expression were associated with the number of 10-repeat alleles. These data provide direct evidence that the VNTR, or another polymorphism in linkage disequilibrium with the VNTR, is involved in regulating expression of this gene." [Abstract]

Feng Y, Wigg KG, Makkar R, Ickowicz A, Pathare T, Tannock R, Roberts W, Malone M, Kennedy JL, Schachar R, Barr CL
Sequence variation in the 3'-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD).
Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4;
The dopamine transporter gene (DAT1) has been reported to be associated with attention-deficit hyperactivity disorder (ADHD) in a number of studies [Cook et al. (1995): Am J Human Genet 56(4):9993-998; Gill et al. (1997): Mol Psychiatry 2(4):311-313; Waldman et al. (1998): Am J Human Genet 63(6):1767-1776; Barr et al. (2001): Biol Psychiatry 49(4):333-339; Curran et al. (2001): Mol Psychiatry 6(4):425-428; Chen et al. (2003): Mol Psychiatry 8(4):393-396]. Specifically, the 10-repeat allele of the 40-bp variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region (UTR) of the gene has been found to be associated with ADHD. There is evidence from in vitro studies indicating that variability in the repeat number, and sequence variation in the 3'-UTR of the DAT1 gene may influence the level of the dopamine transporter protein [Fuke et al. (2001): Pharmacogenomics J 1(2):152-156; Miller and Madras (2002): Mol Psychiatry 7(1):44-55]. In this study, we investigated whether DNA variation in the DAT1 3'UTR contributed to ADHD by genotyping DNA variants around the VNTR region in a sample of 178 ADHD families. These included a MspI polymorphism (rs27072), a DraI DNA change (T/C) reported to influence DAT1 expression levels, and a BstUI polymorphism (rs3863145) in addition to the VNTR. We also screened the VNTR region by direct resequencing to determine if there was sequence variation within the repeat units that could account for the association. Our results indicate that DAT1 is associated with ADHD in our sample but not with alleles of the VNTR polymorphism. We did not find any variation in the sequence for either the 10- or 9-repeat alleles in the probands screened nor did we observe the reported DraI (T/C) variation. Our results therefore refute the possibility of the reported DraI variation or alleles of the VNTR as the functional variants contributing to the disorder. [Abstract]

Cook EH Jr, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, Leventhal BL.
Association of attention-deficit disorder and the dopamine transporter gene.
Am J Hum Genet 1995 Apr;56(4):993-8
"Attention-deficit hyperactivity disorder (ADHD) has been shown to be familial and heritable, in previous studies. As with most psychiatric disorders, examination of pedigrees has not revealed a consistent Mendelian mode of transmission. The response of ADHD patients to medications that inhibit the dopamine transporter, including methylphenidate, amphetamine, pemoline, and bupropion, led us to consider the dopamine transporter as a primary candidate gene for ADHD. To avoid effects of population stratification and to avoid the problem of classification of relatives with other psychiatric disorders as affected or unaffected, we used the haplotype-based haplotype relative risk (HHRR) method to test for association between a VNTR polymorphism at the dopamine transporter locus (DAT1) and DSM-III-R-diagnosed ADHD (N = 49) and undifferentiated attention-deficit disorder (UADD) (N = 8) in trios composed of father, mother, and affected offspring. HHRR analysis revealed significant association between ADHD/UADD and the 480-bp DAT1 allele (chi 2 7.51, 1 df, P = .006). When cases of UADD were dropped from the analysis, similar results were found (Chi 2 7.29, 1 df, P = .007). If these findings are replicated, molecular analysis of the dopamine transporter gene may identify mutations that increase susceptibility to ADHD/UADD. Biochemical analysis of such mutations may lead to development of more effective therapeutic interventions." [Abstract]

Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M.
Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism.
Mol Psychiatry 1997 Jul;2(4):311-3
"Attention deficit hyperactivity disorder (ADHD) is a common condition of childhood the symptoms of which include inattention, excessive motor activity, inpulsivity and distractibility. It is strongly familial and twin and adoption studies suggest that the familiality is due, at least in part, to shared genes. Gillis et al found concordance rates in ADHD for MZ and DZ twins of 81% and 29% respectively. Stimulant drugs (eg, methylphenidate) are effective in the treatment of ADHD and inhibit the dopamine transporter. This has led to the development of a hypodopaminergic hypothesis for the disease. Cook et al examined a 3' variable number of tandem repeat (VNTR) polymorphism at the dopamine transporter gene (DAT1) in a sample of 49 ADHD patients and their parents, using the haplotype relative risk (HRR) method. They found a significant association (chi 2 = 7.29, 1 d.f., P = 0.007) between ADHD and the 480-bp DAT1 VNTR allele. The authors stressed the importance of independent replication and we have achieved this in a study of 40 probands and their parents, using the same robust HRR method. As in the study of Cook et al we found that the 480-bp allele was preferentially transmitted to ADHD probands (chi 2 = 6.07, 1 d.f., P = 0.014)." [Abstract]

Chen CK, Chen SL, Mill J, Huang YS, Lin SK, Curran S, Purcell S, Sham P, Asherson P.
The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample.
Mol Psychiatry 2003 Apr;8(4):393-6
"Genetic variation of the dopamine transporter gene (DAT1) is of particular interest in the study of attention-deficit hyperactivity disorder (ADHD), since stimulant drugs interact directly with the transporter protein. Association between ADHD and the 10-repeat allele of a 40-bp VNTR polymorphism that lies within the 3'-UTR of DAT1 was first reported in 1995, a finding that has been replicated in at least six independent samples from Caucasian populations. We analysed the DAT1 polymorphism in a sample of 110 Taiwanese probands with a DSM-IV diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using TRANSMIT (chi(2)=10.8, 1 d.f., p=0.001, OR=2.9, 95% CI 1.4-6.3). These data give rise to a similar odds ratio to that observed in Caucasian poplulations despite a far higher frequency of the risk allele in this Taiwanese population; 82.3% in the un-transmitted parental alleles and 94.5% in the ADHD probands. These data support the role of DAT1 in ADHD susceptibility among Asian populations." [Abstract]

Purper-Ouakil D, Wohl M, Mouren MC, Verpillat P, Adès J, Gorwood P
Meta-analysis of family-based association studies between the dopamine transporter gene and attention deficit hyperactivity disorder.
Psychiatr Genet. 2005 Mar;15(1):53-9.
INTRODUCTION: Molecular genetic research has mainly focused on the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) genes in attention-deficit hyperactivity disorder (ADHD). A recent meta-analysis showed that the DRD4 gene has a significant role in the vulnerability to ADHD. OBJECTIVES: With an equal number of positive and negative association studies between the 10-repeat of the DAT gene and ADHD, a meta-analysis is required for this other candidate gene. METHODS: We re-analysed the 13 published family-based association studies between ADHD and the DAT gene. Following recent recommendations, different biases were specifically assessed, such as the sample-size effect and the time effect. RESULTS: The meta-analysis showed no significant association between ADHD and the DAT gene (P = 0.21), but an important between-samples heterogeneity (P = 0.0009). Odds ratios above 1 are mostly observed in studies with a small number of informative transmissions, and decrease with larger sample size. CONCLUSIONS: Contrary to what was found for the DRD4 gene, the 10-repeat allele of the DAT gene has at most a minor role in the genetic susceptibility of ADHD. The different biases detected herein probably explain the initial impression of a significant impact of the DAT gene on hyperactivity. [Abstract]

Langley K, Turic D, Peirce TR, Mills S, Van Den Bree MB, Owen MJ, O'donovan MC, Thapar A
No support for association between the dopamine transporter (DAT1) gene and ADHD.
Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4;
Several groups have reported an association between the 10-repeat allele of a dopamine transporter (DAT1) 3'UTR VNTR variant and ADHD but the finding has not been universally observed. An association between DAT1 genotype and stimulant medication response has also been reported although again there are conflicting data. We tested the DAT1 3'VNTR and three SNPs in the putative promoter region of DAT1 for association with ADHD in 263 parent-proband trios. Analyses of genotypes, alleles, and haplotypes were performed using family-based association methods. Case-control analysis of the VNTR in 263 cases and 287 controls was also conducted. In addition, we tested for association between the VNTR marker and stimulant medication response. Comparing allele 10 versus all other alleles combined, no significant association was found with ADHD, using FBAT analysis (chi(2) = 0.1 (df 1), P = 0.9, (odds ratio (OR) = 1.0, 95% CI 0.8-1.2), and case-control analysis (chi(2) = 0.12 (df 2), P = 0.91). No evidence of association with any of the SNPs in the promoter region was found. Haplotype analysis was also non-significant (chi(2) = 3.93, (df 9) global P = 0.85). Finally, no association was found between the DAT 1 VNTR and response to stimulant medication (chi(2) = 1.63 (df 3) P = 0.65). We conclude that the 3' VNTR and three additional promoter variants in DAT1 do not appear to be associated with ADHD, or response to stimulant mediation in our sample. [Abstract]

Barr CL, Xu C, Kroft J, Feng Y, Wigg K, Zai G, Tannock R, Schachar R, Malone M, Roberts W, Nothen MM, Grunhage F, Vandenbergh DJ, Uhl G, Sunohara G, King N, Kennedy JL.
Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder.
Biol Psychiatry 2001 Feb 15;49(4):333-9 [Abstract]

Loo SK, Specter E, Smolen A, Hopfer C, Teale PD, Reite ML.
Functional effects of the DAT1 polymorphism on EEG measures in ADHD.
J Am Acad Child Adolesc Psychiatry. 2003 Aug;42(8):986-93.
"OBJECTIVE: This paper examines whether dopamine transporter gene (DAT1) allele status mediates medication-related change in cognitive and neurophysiological measures among children with attention-deficiency/hyperactivity disorder (ADHD). METHOD: A single 10-mg dose of methylphenidate was given in a double-blind, placebo-controlled fashion to children with ADHD who were seen for cognitive testing and EEG recording. Buccal samples were obtained and genotyped for the DAT1 polymorphism. RESULTS: DAT1 allele status was associated with performance on a sustained attention task and medication-related EEG changes. Compared with those with one or more copies of the DAT1 9-repeat allele (9R), children with two copies of the 10-repeat allele (10R) exhibited poorer performance on the vigilance task. In addition, children with 10R exhibited medication-related EEG changes of increased central and parietal beta power, decreased right frontal theta power, and lower theta/beta ratios; 9R carriers showed the opposite pattern. CONCLUSIONS: The data suggest that the DAT1 polymorphism mediates medication-related changes in cortical activity among children with ADHD." [Abstract]

Oh KS, Shin DW, Oh GT, Noh KS.
Dopamine transporter genotype influences the attention deficit in Korean boys with ADHD.
Yonsei Med J. 2003 Oct 30;44(5):787-92. [Abstract] [Full Text]

Rohde LA, Roman T, Szobot C, Cunha RD, Hutz MH, Biederman J.
Dopamine transporter gene, response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: A pilot study.
Synapse 2003 May;48(2):87-9
"The homozygosity of the 10-repeat allele at dopamine transporter gene (DAT1) seems to be associated with a poor response to methylphenidate (MPH) in children with attention-deficit/hyperactivity disorder (ADHD). This pilot study aimed to simultaneously assess polymorphisms at DAT1, response to MPH, and neuroimaging. Only ADHD children with at least a moderate response to MPH were included. Significantly higher regional cerebral blood flows assessed by single photon emission computerized tomography (SPECT) were detected in medial frontal and left basal ganglia areas in children with homozygosity for the 10-repeat allele at DAT1 gene (n = 4) than in children without this genotype (n = 4) (P < 0.05). These findings provide a preliminary connection between pharmacogenetics and neurobiological investigations on stimulant treatment of ADHD." [Abstract]

Kirley A, Lowe N, Hawi Z, Mullins C, Daly G, Waldman I, McCarron M, O'Donnell D, Fitzgerald M, Gill M.
Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD.
Am J Med Genet. 2003 Aug 15;121B(1):50-4.
"Several studies have implicated the dopamine transporter gene (DAT1) as conferring susceptibility to attention deficit hyperactivity disorder (ADHD), in particular, a VNTR situated at the 3' end of the gene. In addition, the 10-repeat VNTR allele associated with ADHD has been reported to be associated with an over-active transporter protein (DAT). Thus children possessing this variant might be particularly responsive to methylphenidate, a drug known to act by blocking DAT. We have examined this hypothesis and now report an association between the 10-repeat VNTR DAT1 polymorphism and retrospectively rated methylphenidate response in a sample of 119 Irish children with ADHD (chi(2) = 7.918, df = 1, P = 0.005). Our findings suggest a role for the 10-repeat DAT1 risk allele in medication response and may help to predict positive clinical outcome in ADHD." [Abstract]

Muglia P, Jain U, Inkster B, Kennedy JL.
A quantitative trait locus analysis of the dopamine transporter gene in adults with ADHD.
Neuropsychopharmacology 2002 Oct;27(4):655-62
"Numerous lines of evidence have shown that attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, whether it is considered as a category or a dimension. We tested for an association between the dopamine transporter gene (DAT1) and ADHD considering the disorder as categorical as well as a continuous trait. Genotypes for the DAT1 variable number of tandem repeat (VNTR) alleles, along with Brown Attention Deficit Disorder Scale (BADDS) and Wender Utah Rating Scale (WURS) scores were available for 152 adult ADHD patients. In 72 of these patients DNAs from at least one parent were accessible to perform a family-based analysis (FBAT). The mean quantitative trait values of the whole sample of singleton patients were compared among the specific genotype groups using ANOVA. The family-based analysis did not reveal any association between DAT1 alleles and ADHD either when it was considered as a dichotomous trait (Z = 0.16, p =.86) or as a continuous trait (Wender Scale Z = -1.67, p =.09; Brown ADD Scale Z = 0.28, p =.77). No significant differences were detected in the mean symptom scores among the specific genotype groups. The results from our study do not support a major role for the DAT1 VNTR alleles in our sample of adult ADHD. In view of several positive reports in child ADHD, more work is required to elucidate the potential role of the DAT1 VNTR as a risk factor in ADHD." [Abstract]

Curran S, Mill J, Tahir E, Kent L, Richards S, Gould A, Huckett L, Sharp J, Batten C, Fernando S, Ozbay F, Yazgan Y, Simonoff E, Thompson M, Taylor E, Asherson P.
Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples.
Mol Psychiatry 2001 Jul;6(4):425-8
"Molecular genetic studies in attention deficit hyperactivity disorder (ADHD) have focussed on candidate genes within the dopamine system, which is thought to be the main site of action of stimulant drugs, the primary pharmacological treatment of the disorder. Of particular interest are findings with the dopamine transporter gene (DAT1), since stimulant drugs interact directly with the transporter protein. To date, there have been eight published association studies of ADHD with a 480 base-pair allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the gene, five that support an association and three against. We have analysed the same VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children with DSM-IV ADHD, using the transmission disequilibrium test (TDT). Results from the UK (chi(2) = 8.97, P = 0.001, OR = 1.95), but not the Turkish sample (chi(2) = 0.93, P = 0.34) support association and linkage between genetic variation at the DAT1 locus and ADHD. When considered alongside evidence from other published reports, there is only modest evidence for the association, consistent with a very small main effect for the 480-bp allele (chi(2) = 3.45, P = 0.06, OR = 1.15), however we find significant evidence of heterogeneity between the combined dataset (chi(2) = 22.64, df = 8, P = 0.004)." [Abstract]

Simsek M, Al-Sharbati M, Al-Adawi S, Ganguly SS, Lawatia K
Association of the risk allele of dopamine transporter gene (DAT1*10) in Omani male children with attention-deficit hyperactivity disorder.
Clin Biochem. 2005 Aug;38(8):739-42.
OBJECTIVES:: To determine the frequency of the VNTR alleles in the human dopamine transporter gene (DAT1) in the Omani population and to investigate association of the VNTR alleles with attention-deficit hyperactivity disorder (ADHD). DESIGN AND METHODS:: 92 Omani children with ADHD and 110 healthy Omani subjects were genotyped for the DAT1-VNTR polymorphism in a case-control study using two independent PCR tests (one developed in our laboratory) followed by agarose gel electrophoresis. RESULTS AND CONCLUSIONS:: We determined the DAT1-VNTR alleles in 202 Omani subjects. There were two common alleles (DAT1*9 and *10) and five rare ones. The DAT1*10 allele distribution was essentially the same both in the control (60.9%) and the patient group (64.6%). There was, however, a relatively higher occurrence of the DAT1*10 allele in ADHD males (69.4%) than females (55%), but this gender difference was not present in the control group (males 60%, females 62%). [Abstract]

Kahn RS, Khoury J, Nichols WC, Lanphear BP.
Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors.
J Pediatr. 2003 Jul;143(1):104-10.
"OBJECTIVE: To examine the joint effects of a dopamine transporter (DAT) polymorphism and maternal prenatal smoking on childhood hyperactivity-impulsivity and inattentiveness. STUDY DESIGN: A cohort of 161 children was followed prospectively from age 6 months to 60 months. Primary outcomes were the DSM-IV hyperactive-impulsive and inattentive scales of the Conners' Parent Rating Scale Revised-Long Version (CPRS R:L). A secondary outcome was the oppositional scale. Predictors included DAT genotype and maternal report of prenatal smoking. Children homozygous for the 480-bp DAT allele (DAT +/+) were compared with all other children (DAT +/- or -/-). RESULTS: In multivariate analyses, children with both prenatal smoke exposure and the DAT +/+ genotype had significantly elevated hyperactive-impulsive scores (beta, 7.5; SE, 2.9; P<.01) compared with children with no smoke exposure and DAT +/- or -/-. Inattentive scores were not significantly elevated in this group, but oppositional scores were a full standard deviation higher. Neither prenatal smoke exposure alone nor DAT +/+ genotype alone was significantly associated with increased scores. CONCLUSIONS: Child hyperactivity-impulsivity and oppositional behaviors were associated with a DAT polymorphism but only when the child also had exposure to maternal prenatal smoking. This study emphasizes the importance of incorporating environmental cofactors in genetic studies of attention deficit hyperactivity disorder." [Abstract]

Cornish KM, Manly T, Savage R, Swanson J, Morisano D, Butler N, Grant C, Cross G, Bentley L, Hollis CP
Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample.
Mol Psychiatry. 2005 Jul;10(7):686-98.
Association between attention-deficit hyperactivity disorder (ADHD) and the 10-repeat allele of the dopamine transporter gene (DAT1) has been reported in independent clinical samples using a categorical clinical definition of ADHD. The present study adopts a quantitative trait loci (QTL) approach to examine the association between DAT1 and a continuous measure of ADHD behaviours in a general-population sample, as well as to explore whether there is an independent association between DAT1 and performance on neuropsychological tests of attention, response inhibition, and working memory. From an epidemiological sample of 872 boys aged 6-11 years, we recruited 58 boys scoring above the 90th percentile for teacher reported ADHD symptoms (SWAN ADHD scale) and 68 boys scoring below 10th percentile for genotyping and neuropsychological testing. A significant association was found between the DAT1 homozygous 10/10-repeat genotype and high-scoring boys (chi(2)square=4.6, P<0.03; odds ratio=2.4, 95% CI 1.1-5.0). Using hierarchical linear regression, a significant independent association was found between the DAT1 10/10-repeat genotype and measures of selective attention and response inhibition after adjusting for age, IQ, and ADHD symptoms. There was no association between DAT1 and any component of working memory. Furthermore, performance on tasks of selective attention although associated with DAT1 was not associated with SWAN ADHD high scores after controlling for age and IQ. In contrast, impairment on tasks that tapped sustained attention and the central executive component of working memory were found in high-scoring boys after adjusting for age and IQ. The results suggest that DAT1 is a QTL for continuously distributed ADHD behaviours in the general population and the cognitive endophenotype of response inhibition. [Abstract]

Oh KS, Shin DW, Oh GT, Noh KS.
Dopamine transporter genotype influences the attention deficit in Korean boys with ADHD.
Yonsei Med J. 2003 Oct 30; 44(5): 787-92.
"Attention appears to be inheritable, stable and influenced by genetic factors. The use of the Continuous Performance Test (CPT), as an endophenotypic measure, is valuable for genetic studies because it may show increased sensitivity to specific dimensions in attention deficit hyperactivity disorder. However, few studies have been designed to examine the influence of the genotype on attention level measured by CPT in ADHD patients. This study examinee the difference between 10/10 and 10/* genotype in the attention deficits measured by the CPT in ADHD patients. Forty-four unrelated ADHD patients were recruited from the psychiatric outpatients' clinic at Kangbuk Samsung Hospital. Two child psychiatrists made the diagnoses of ADHD using the DSM- IV diagnostic criteria. The genomic DNA was extracted from the blood, and analyzed to determine the genotype. A 40- base pair variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region was amplified. The attention deficits were measured by the test of variables of attention (T.O.V.A.). Between the 10/10 genotype and 10/* genotype, standard scores of the T.O.V.A were compared using a Mann-Whiney test. A comparison with the 10/10 genotype and 10/* genotype showed that those patients with the 10/10 genotype made less omission errors in the first quarter of the test (p < 0.05, by Mann-Whiney test). No significant differences were observed in the errors of commission, response time, variability. This study found that the 10/10 genotype made less omission errors on the T.O.V.A. This suggests that the dopamine transporter genotype influences the attention deficits measured by T.O.V.A." [Abstract]

Qian QJ, Wang YF, Zhou RL, Yang L, Li J
[Association studies of G352A polymorphism of dopamine transporter gene in Han Chinese attention deficit hyperactivity disorder patients.]
Beijing Da Xue Xue Bao. 2004 Dec;36(6):626-9.
OBJECTIVE: To investigate association of the new polymorphism G352A in the dopamine transporter gene (DAT1) exon 15 with attention deficit hyperactivity disorder (ADHD) in Han Chinese children. METHODS: The new mutant polymorphism G352A in the dopamine transporter gene (DAT1) exon 15 was found by the fluorescently-labeled dye-terminators assay. The study samples were comprised of 337 ADHD children, 207 unrelated controls and 201 integrated ADHD trios (included proband and biological parents). Associations of polymorphisms with ADHD and its subtypes were examined by: (i) comparing cases and controls; and (ii) using family-based association study in transmission-disequilibrium test (TDT). RESULTS: The allele frequencies at the DAT1 G352A locus in the control samples were 79.5% for 352G and 20.5% for 352A respectively. Association studies revealed no association between G352A in exon 15 of DAT1 and ADHD. But after a stratification by gender, there was possible association between G352A and ADHD girls: the 352G allele had a tendency to be preferentially transmitted to ADHD girls. CONCLUSION: There is no association between G352A, the new polymorphism, in exon 15 of DAT1 and ADHD. The 352G allele has a tendency to be preferentially transmitted to ADHD girls, but the findings require replication before drawing a definitive conclusion. [Abstract]

Qian Q, Wang Y, Zhou R, Yang L, Faraone SV
Family-based and case-control association studies of DRD4 and DAT1 polymorphisms in Chinese attention deficit hyperactivity disorder patients suggest long repeats contribute to genetic risk for the disorder.
Am J Med Genet B Neuropsychiatr Genet. 2004 Jul 1;128(1):84-9.
Molecular genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated the variable number of tandem repeat (VNTR) polymorphisms of two candidate genes, the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1). We sought to determine if these genes were relevant to the etiology of ADHD in China by using both family-based (N = 202 nuclear ADHD families) and case-control (N = 340 ADHD cases, and 226 controls) association study designs. Diagnoses and subtypes were ascertained according to Clinical Diagnostic Interview Scales (CDIS) using DSM-IV criteria. The repeat numbers at the DRD4 VNTR ranged from 2 to 6 repeats in the Han Chinese controls, with the most common being the 4-repeat (77%) and 2-repeat (19.4%) alleles. Neither the 7-repeat allele nor longer repeats were found. For the DAT1 VNTR, the repeat numbers ranged from 6 to 7 repeats and 9 to 11 repeats. The 10-repeat allele was the most frequent (90.7%). The long-repeat alleles of DRD4 (ranging from 4 to 6 repeats) and DAT1 (ranging from 11 to 12 repeats), were present more frequently in ADHD probands than controls (P < 0.05), although there was no significant allelic association when the alleles were analyzed separately from each other and there findings were not supported by within family tests of association. An exploratory stratification by gender suggests that long-repeat alleles of DRD4 and DAT1 may increase the risk for ADHD in Han Chinese children. [Abstract]

Kirley A, Hawi Z, Daly G, McCarron M, Mullins C, Millar N, Waldman I, Fitzgerald M, Gill M.
Dopaminergic system genes in ADHD: toward a biological hypothesis.
Neuropsychopharmacology 2002 Oct;27(4):607-19
"Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD). Several genetic association studies have been published, but so far, no DNA variants have been unequivocally demonstrated as contributing to ADHD susceptibility. Four dopamine related gene loci have been implicated, however: DAT 1, DRD 4, DBH, and DRD 5. Each of these may influence the liability of ADHD to a small degree. Notably, all are involved in signal transduction at the neuronal synapse. In this article, we investigate as candidate genes for ADHD, DNA polymorphisms at dopamine receptors, the dopamine transporter, and genes known to be involved in dopamine synthesis and metabolism. In a recent article, we confirmed the previously reported association of DAT 1 (480 bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD 5 (148 bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4 bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH (allele 2) and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD 1, DRD 2 (Taq I), DRD 3, DRD 4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH (allele 2) and a nonsignificant trend for paternal transmission for DRD 2 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses." [Abstract]

Huang YS, Lin SK, Wu YY, Chao CC, Chen CK.
A family-based association study of attention-deficit hyperactivity disorder and dopamine D2 receptor TaqI A alleles.
Chang Gung Med J. 2003 Dec;26(12):897-903.
"CONCLUSION: The results of this study do not support DRD2 playing a major role in Taiwanese children with ADHD." [Abstract]

Hawi Z, Lowe N, Kirley A, Gruenhage F, Nothen M, Greenwood T, Kelsoe J, Fitzgerald M, Gill M.
Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci.
Mol Psychiatry 2003 Mar;8(3):299-308
"Abnormalities in dopaminergic neurotransmission are now accepted as factors in predisposing to ADHD. Evidence of associations between dopamine transporter gene polymorphism and ADHD was first reported by Cook et al. We confirmed the DAT1 association and also identified two additional susceptibility loci at the DRD5 and DBH. Notably, none of the associated variants at these three genes are known to be expressed. Other variants within or closely mapped to the associated alleles are likely to be relevant. In this investigation, we analyse additional markers creating a high-density map across and flanking these genes, and measure intermarker linkage disequilibrium (LD). None of the newly examined markers were more strongly associated with ADHD. At DAT1, the pattern of intermarker LD and haplotype association with the phenotype between exon 9 and the 3' of the gene suggests that the functional variant at DAT1 may be located to this region. For DRD5, three markers, covering a region of approximately 68 kb including the single DRD5 exon are all associated with disease, and thus do not provide localizing information. However, the data for DBH point to a region close to the centre of the gene. Correlation between D' and physical distance was observed between markers at DAT1 and DRD5 for distances less than 50 kb. This was not the case for DBH, where LD breakdown was observed between the intron 5 and intron 9 polymorphisms although they are only 9 kb apart. Further genetic analysis is unlikely to refine the location of susceptibility variants and functional assessment of variants within associated regions is required." [Abstract]

Daly G, Hawi Z, Fitzgerald M, Gill M.
Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children.
Mol Psychiatry 1999 Mar;4(2):192-6
"Attention deficit hyperactivity disorder (ADHD) is a common disorder of childhood characterized by inattention, excessive motor activity, impulsivity, and distractibility. It is associated with serious disability in children, adolescents and adults. The etiology of the disorder is unknown, but it has a strong genetic component. Pharmacological and biochemical studies have suggested that dopaminergic and noradrenergic systems are involved. Using a sample of affected children and their parents we have found preferential transmission of alleles at polymorphisms at the dopamine transporter (DAT1), RR=1.2 (1.05-1.37), P=0.006, re-confirming and extending our previous findings for DAT1 (new sample one-tailed P=0.039); dopamine-beta-hydroxylase (DBH), RR=1.31 (1.09-1.56), P=0.0027; and the dopamine D5 receptor (DRD5), RR=1.67 (1.29-2.15), P=0.00005. Transmission of the 'associated' alleles at DAT1 and DBH is stronger in familial cases, RR(DAT1)=1.29 (1.04-1.59), RR(DBH)=1.49 (1.10-2.00), but for DRD5, transmission is stronger in non-familial cases, RR=1.59 (1.05-2.42). TDT analysis of complete trios supports the HHRR analysis, with P<0.05, for DAT1 P<0.005 and DBH and P<0.01 for DRD5. Attributable fractions for DAT1, DBH and DRD5 are calculated at 0.08, 0.12 and 0.20 respectively." [Abstract]

Tahir E, Yazgan Y, Cirakoglu B, Ozbay F, Waldman I, Asherson PJ.
Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children.
Mol Psychiatry 2000 Jul;5(4):396-404
"The search for genetic factors predisposing to Attention Deficit Hyperactivity Disorder (ADHD) has focused on genes that regulate dopaminergic pathways such as dopamine receptors and enzymes that regulate levels of dopamine in the synapse. There have been several reports of association between ADHD and polymorphic variants within or near DRD4, DRD5, DAT1, DBH and COMT. In this study we set out to investigate specific alleles of DRD4 and DRD5, previously reported to be associated with ADHD, in a sample of Turkish children with DSM-IV ADHD children, as well as their relation to methylphenidate response and dimensional measures of symptom domains. One hundred and four independent trios and seven dyads were analysed using the transmission disequilibrium test (TDT). We found increased transmission of the DRD4 7-repeat allele (DRD4*7) (TDT chi2 = 2.79, P = 0.047). Given that we were testing specific a priori hypotheses regarding the associated alleles, we have used one-tailed P-values throughout. There was evidence of an interaction with methlyphenidate (MPH) response and analysis of the sample excluding non-responders revealed more significant evidence for the association (TDT chi2 = 4.48, P = 0.017). We also detected a trend for linkage and association in the DRD5 polymorphism (TDT chi2 = 2. 38, P = 0.06). Similar findings were obtained in relation to MPH response as analysis of MPH responders alone gave rise to a more significant association than that of the group as a whole (TDT chi2 = 4.9, P = 0.013). t-Test and logistic regression TDT analyses of DRD4*7 transmission with respect to dimensional rating scales of hyperactivity and impulsivity showed an inverse relation suggesting that in this sample DRD4*7 is associated with a lower level of ADHD symptomatology. While this may be due to stratification along a dimension of severity such that severe cases belong to a more extreme group with other specific genetic and environmental causes, similar to the model for low cognitive ability, it is more likely the result of a chance selection bias in this sample." [Abstract]

Manor I, Corbex M, Eisenberg J, Gritsenkso I, Bachner-Melman R, Tyano S, Ebstein RP.
Association of the dopamine D5 receptor with attention deficit hyperactivity disorder (ADHD) and scores on a continuous performance test (TOVA).
Am J Med Genet. 2004 May 15;127B(1):73-7.
"Towards further clarifying the role of dopamine D5 receptor (DRD5) microsatellite polymorphism in the etiology of ADHD, we used a robust family based strategy to test for association between DRD5 and this disorder. Additionally, a neuropsychological mechanism by which this allele may confer risk was explored by examining the relationship between DRD5 genotype and scores on a continuous performance test. DNA was obtained from 164 probands and their parents. Additionally, the majority of these probands were administered a computerized continuous performance test, the Test Of Variables of Attention (TOVA). We first confirmed preferential transmission (TDT chi(2) = 7.02, P = 0.008) of the 148 base pair allele in 155 informative transmissions (94 transmitted and 61 non-transmitted 148 bp allele). Additionally, we used a family-based association test (FBAT) and observed significant multivariate association using FBAT between TOVA scores before methylphenidate administration and the DRD5 microsatellite polymorphism across all four TOVA variables: multi-allelic, multivariate test chi(2) = 16.32, P = 0.037 when the 148 bp allele was compared to all others (collapsed genotype) that was also significant (chi(2) = 59.20, P = 0.025) when all 14 alleles (full genotype) were analyzed. Following methylphenidate, no significant association was observed (chi(2) = 12.08, P = 0.147 for 148 bp versus all others) and, similarly, for all 14 alleles (chi(2) = 47.18, P = 0.343). In summary, the main finding of this report is that the DRD5 repeat polymorphism confers a small but significant risk for ADHD consistent with previous reports. Provisional results in this single investigation suggest that the DRD5 microsatellite also affects performance scores on the TOVA." [Abstract]

Lowe N, Kirley A, Hawi Z, Sham P, Wickham H, Kratochvil CJ, Smith SD, Lee SY, Levy F, Kent L, Middle F, Rohde LA, Roman T, Tahir E, Yazgan Y, Asherson P, Mill J, Thapar A, Payton A, Todd RD, Stephens T, Ebstein RP, Manor I, Barr CL, Wigg KG, Sinke RJ, Buitelaar JK, Smalley SL, Nelson SF, Biederman J, Faraone SV, Gill M.
Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes.
Am J Hum Genet. 2004 Feb;74(2):348-56. Epub 2004 Jan 19.
"Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes." [Abstract] [Full Text]

Kustanovich V, Ishii J, Crawford L, Yang M, McGough JJ, McCracken JT, Smalley SL, Nelson SF.
Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5.
Mol Psychiatry. 2003 Dec 16 [Epub ahead of print]
"Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop ADHD. Reports implicate variants of genes important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5. In the present study, we genotyped a large multiplex sample of ADHD affected children and their parents for polymorphisms in genes previously reported to be associated with ADHD. Associations were tested by the transmission disequilibrium test (TDT). The sample is sufficient to detect genotype relative risks (GRRs) for putative risk alleles. The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed a significant bias in transmission of the insertion (chi(2)=7.58, P=0.006) as suggested by an analysis of a subset of these families. The seven repeat allele of the DRD4 48-bp repeat polymorphism (DRD4.7) was not significantly associated with ADHD in the large sample in contrast to our earlier findings in a smaller subset. We replicate an association of a dinucleotide repeat polymorphism near the DRD5 gene with ADHD by showing biased nontransmission of the 146-bp allele (P=0.02) and a trend toward excess transmission of the 148-bp allele (P=0.053). No evidence for an association was found for polymorphisms in DRD2 or DAT1 in this sample. The DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing a significant association in this large sample of predominantly multiplex families with ADHD, with estimated GRRs of 1.7 and 1.37, respectively." [Abstract]

Bakker SC, van der Meulen EM, Oteman N, Schelleman H, Pearson PL, Buitelaar JK, Sinke RJ
DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):50-2.
Recent meta-analyses have indicated that the dopamine transporter gene (DAT1) and the dopamine receptor genes D4 (DRD4) and D5 (DRD5) are associated with attention-deficit hyperactivity disorder (ADHD), although single studies frequently failed to show significant association. In a family-based sample of 236 Dutch children with ADHD, we have investigated the previously described variable number of tandem repeat (VNTR) polymorphisms and two additional microsatellites at the DAT1 and DRD4 loci. DRD5 was investigated using the microsatellite that was previously found to be associated. Transmission disequilibrium tests (TDTs) did not show preferential transmission of alleles or two-marker haplotypes to affected offspring. These data suggest that DAT1, DRD4, and DRD5 do not contribute substantially to ADHD in the Dutch population. [Abstract]

Mill J, Curran S, Richards S, Taylor E, Asherson P.
Polymorphisms in the dopamine D5 receptor (DRD5) gene and ADHD.
Am J Med Genet. 2004 Feb 15;125B(1):38-42.
"There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A microsatellite located near the dopamine D5 receptor (DRD5) gene has been associated with ADHD in a number of studies, but other polymorphisms within the vicinity of this gene have not been examined. In this study we genotyped three microsatellites spanning the DRD5 region in a large clinical sample. Overall, we found little evidence to support a role for DRD5 in ADHD. We found no evidence of association with either the previously associated DRD5 marker, or a repeat in the promoter region of the gene. We did, however, find significant association for an allele of D4S615, a dinucleotide repeat located 131 kb 3' of DRD5 that has been previously associated with schizophrenia. A global test incorporating all alleles of this marker, however, was not significant and thus this finding needs replication before any conclusions can be made." [Abstract]

Misener VL, Luca P, Azeke O, Crosbie J, Waldman I, Tannock R, Roberts W, Malone M, Schachar R, Ickowicz A, Kennedy JL, Barr CL.
Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder.
Mol Psychiatry. 2004 May;9(5):500-9.
"Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (-1251HaeIII), D1P.6 (-800HaeIII), D1.1 (-48DdeI) and D1.7 (+1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P=0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene." [Abstract]