Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, Nothen MM, Maffei P, Franke P, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Lesch KP.
Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder.
Hum Mol Genet 1999 Apr;8(4):621-4
"A genetic contribution to the pathogenesis of panic disorder has been demonstrated by clinical genetic studies. Molecular genetic studies have focused on candidate genes suggested by the molecular mechanisms implied in the action of drugs utilized for therapy or in challenge tests. One class of drugs effective in the treatment of panic disorder is represented by monoamine oxidase A inhibitors. Therefore, the monoamine oxidase A gene on chromosome X is a prime candidate gene. In the present study we investigated a novel repeat polymorphism in the promoter of the monoamine oxidase A gene for association with panic disorder in two independent samples (German sample, n = 80; Italian sample, n = 129). Two alleles (3 and 4 repeats) were most common and constituted >97% of the observed alleles. Functional characterization in a luciferase assay demonstrated that the longer alleles (3a, 4 and 5) were more active than allele 3. Among females of both the German and the Italian samples of panic disorder patients (combined, n = 209) the longer alleles (3a, 4 and 5) were significantly more frequent than among females of the corresponding control samples (combined, n = 190, chi2 = 10.27, df = 1, P = 0.001). Together with the observation that inhibition of monoamine oxidase A is clinically effective in the treatment of panic disorder these findings suggest that increased monoamine oxidase A activity is a risk factor for panic disorder in female patients." [Abstract]

Sand P, Lesch KP, Catalano M, Bosi M, Syagailo YV, Okladnova O, Di Bella D, Maffei P, Heils A, Friess F, Politi E, Nothen MM, Franke P, Stober G, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Riederer P, Deckert J.
Polymorphic MAO-A and 5-HT-transporter genes: analysis of interactions in panic disorder.
World J Biol Psychiatry 2000 Jul;1(3):147-50
"Recurrent panic attacks, anticipatory anxiety and phobic avoidance characterise panic disorder. The influence of genetic factors on liability to the disease has been the object of several linkage and association studies and appears to relate to an oligo- or polygenic rather than a monogenic mode of inheritance. Recently, an excess of high activity monoamine oxidase A (MAO-A) gene promoter alleles was found in female patients with panic disorder. An analysis of possible synergistic effects of the MAO-A gene promoter variant and the short serotonin transporter (5-HTT) gene promoter variant in panic disorder was performed in a German and an Italian sample (combined panic disorder n = 144, combined controls n = 175). There was no significant difference in odds ratios, suggesting that the observed increase of genetic liability by the long MAO-A gene promoter allele is not modified by the 5-HTT gene promoter polymorphism." [Abstract]

Tadic A, Rujescu D, Szegedi A, Giegling I, Singer P, Moller HJ, Dahmen N.
Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression.
Am J Med Genet 2003 Feb 15;117B(1):1-6
"This study was conducted to detect a possible association of a T941G single nucleotide polymorphism (SNP) in the monoamine oxidase A (MAOA) gene with generalized anxiety disorder (GAD), panic disorder (PD), or major depression (MD). Fifty GAD patients (34 females and 16 males), 38 PD patients (21 females and 17 males), and 108 MD patients (80 females and 28 males) were included. The comparison group consisted of 276 (132 females and 144 males) unrelated healthy individuals. The 941T allele was over-represented in patients suffering from GAD (chi(2) = 6.757; df = 1; P < 0.01, not corrected for multiple testing) when compared to healthy volunteers. No association was observed in MD or PD. This is the first study specifically analyzing the MAOA G941T polymorphism in GAD and thus needs to be replicated in an independent sample. However, the results are in line with previous data suggesting an association between the MAOA locus and regulation of complex human behavior." [Abstract]

Maron E, Tasa G, Tõru I, Lang A, Vasar V, Shlik J
Association between serotonin-related genetic polymorphisms and CCK-4-induced panic attacks with or without 5-hydroxytryptophan pretreatment in healthy volunteers.
World J Biol Psychiatry. 2004 Jul;5(3):149-54.
Genetic regulation of the function of serotonin (5-HT) may be important for the neurobiology of panic disorder. In order to evaluate the influence of 5-HT-related gene variants on the vulnerability to panic attacks, we genotyped 32 healthy volunteers who participated in the study of the effect of 5-hydroxytryptophan on panic attacks induced with cholecystokinin tetrapeptide (CCK-4). The polymorphisms of interest included those of 5-HT transporter (5-HTTLPR) and monoamine oxidase A (MAO-A promoter region) genes. The results showed significant associations between certain genotypes and panic rate in females but not in male volunteers. Specifically, there was a significantly lower rate of CCK-4-induced panic attacks in female subjects who had MAO-A longer alleles or 5-HTTLPR short allele gene variants. These data suggest that functional genetic polymorphisms of the 5-HT system may influence the vulnerability to panic attacks and add to the growing evidence of inhibitory function of 5-HT in the neuronal circuitry of panic. [Abstract]

Gelernter J, Bonvicini K, Page G, Woods SW, Goddard AW, Kruger S, Pauls DL, Goodson S.
Linkage genome scan for loci predisposing to panic disorder or agoraphobia.
Am J Med Genet 2001 Aug 8;105(6):548-57
"We conducted a 10 cM linkage genome scan in a set of 20 American pedigrees (153 subjects), ascertained through probands with panic disorder (PD). Several anxiety disorders segregate in these families; they were diagnosed on the basis of Schedule for Affective Disorders and Schizophrenia interview. In this article, we describe results for panic disorder and agoraphobia, which are closely related, common, heritable anxiety disorders. This is the first complete linkage genome scan for agoraphobia and the third for PD. A total of 407 markers (389 autosomal, 18 X chromosome) were genotyped. Multipoint LOD score and NPL analysis were completed using GENEHUNTER2. For PD, two genomic regions meet criteria for suggestive linkage. One of these regions is on chromosome 1 (LOD score = 2.04). This region coincides with a region that generated a LOD score of 1.1 in a previous genome scan by Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. The other (LOD score = 2.01) is located on chromosome 11p and occurs at marker CCKBR, one of eight candidate genes examined. For agoraphobia, the most promising potential linkage was on chromosome 3 (NPL score = 2.75; P = 0.005). This was accounted for primarily by a single family that by itself generated an NPL score of 10.01 (P = 0.0039) and a LOD score of 2.10. These results provide initial evidence for a genetic locus on chromosome 3 that contributes to risk for agoraphobia. They also support suggestive linkage to two risk loci for panic disorder. Additional potential loci were identified with lesser statistical support; several of these were consistent with previously reported panic disorder linkage results. Overall, the results presented here suggest that PD and agoraphobia are complex traits that share some, but not all, of their susceptibility loci." [Abstract]

Ebihara M, Ohba H, Hattori E, Yamada K, Yoshikawa T.
Transcriptional activities of cholecystokinin promoter haplotypes and their relevance to panic disorder susceptibility.
Am J Med Genet 2003 Apr 1;118B(1):32-5
"We previously identified a polymorphic compound short tandem repeat (STR) in the 5'-regulatory region of the cholecystokinin (CCK) gene, and showed that when the STRs were classified into three groups based on length and linkage disequilibrium behavior with neighboring variants, the medium class allele was significantly associated with panic disorder. The present study examined the transcriptional activity of the CCK promoter construct containing the STR and downstream -188A/G variation. The STRs acted as transcriptional repressors with a similar potency among the three classes, but the long (L) class STR exhibited a synergistic effect on decreasing promoter activity when combined with -188G. The haplotype composed of the L class of STR and -188G was significantly less frequent in panic disorder (P = 0.0032; odds ratio, 95% confidence interval = 0.06, 0.01-0.69). These results suggest that the L-(-188G) haplotype may act as a protective factor against panic by reducing the expression of anxiogenic CCK." [Abstract]

Hattori E, Ebihara M, Yamada K, Ohba H, Shibuya H, Yoshikawa T.
Identification of a compound short tandem repeat stretch in the 5'-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia.
Mol Psychiatry 2001 Jul;6(4):465-70
"The cholecystokinin gene (CCK) is thought to play a role in the pathogenesis of both panic disorder and schizophrenia. In this study, we have extended the 5'-upstream sequence of the CCK gene, and identified a compound short tandem repeat (STR), located approximately -2.2 to -1.8 kb from the cap site. This STR was found to be polymorphic with ten different allele lengths. Case-control studies using 73 panic patients, 305 schizophrenics and 252 controls showed a significant allelic association with panic disorder (P = 0.025), but not with schizophrenia. Dividing the STR alleles into three classes according to length, Long (L), Medium (M) and Short (S), produced strong genotypic (MM) (nominal P = 0.0014) and allelic (M) (nominal P = 0.0079) associations with panic disorder. screening the newly extended promoter region detected not only the previously identified -36c>t and -188a>g single nucleotide polymorphisms (SNPs) but a new rare snp, -345g>C. Neither of the former two SNPs showed significant association with either panic disorder or schizophrenia. Haplotypic distributions of the STR and SNPs -188 and -36 were significantly different between panic samples and controls (P = 0.0003). These findings suggest that the novel STR or a nearby variant may confer susceptibility to the development of panic disorder." [Abstract]

Kennedy JL, Bradwejn J, Koszycki D, King N, Crowe R, Vincent J, Fourie O.
Investigation of cholecystokinin system genes in panic disorder.
Mol Psychiatry 1999 May;4(3):284-5
"There is evidence for the role of the cholecystokinin (CCK) neurotransmitter system in the neurobiology of panic disorder (PD). The CCK receptor agonist, CCK-tetrapeptide (CCK-4) fulfills criteria for a panicogenic agent and there is evidence that PD might be associated with an abnormal function of the CCK system. For example, PD patients show an enhanced sensitivity to CCK-4, and exhibit lower CSF and lymphocyte CCK concentration as compared to healthy controls (reviewed by Bradwejn et al.). Also, untreated PD patients display an increased CCK-4-induced intracellular Ca2+ mobilization in T cells relative to treated PD, depression and schizophrenia. The CCK receptors have been classified into two subtypes: CCK-A and CCK-B. We report here a study of polymorphisms in the CCK pre-pro hormone gene (CCK), CCK-AR, and CCK-BR in DSM-IV panic patients (n = 99) vs controls matched for gender and ethnicity. The CCK polymorphism revealed no association with PD. We identified a new polymorphism for the CCK-A receptor gene, and tested it in our sample, with negative results. A single nucleotide polymorphism has been found in the coding region of the CCK-B receptor gene (CCK-BR) and D Collier (personal communication) identified a highly polymorphic dinucleotide (CT)n microsatellite in the 5' regulatory region. For the CCK-B receptor gene polymorphism, PD patients showed a significant association. Our genetic dissection of the CCK system thus far suggests that the CCK-B receptor gene variation may contribute to the neurobiology of panic disorder." [Abstract]

Miyasaka K, Yoshida Y, Matsushita S, Higuchi S, Shirakawa O, Shimokata H, Funakoshi A
Association of cholecystokinin-A receptor gene polymorphisms and panic disorder in Japanese.
Am J Med Genet B Neuropsychiatr Genet. 2004 May 15;127(1):78-80.
Several lines of evidence have suggested that naturally occurring alterations in cholecystokinin (CCK) systems could contribute to the development of panic disorder (PD). Among recent investigations, polymorphisms of the CCK and CCK-B receptor (R) genes were investigated, but the results were inconclusive. We recently cloned the genomic structures of human CCK-AR, and determined the transcriptional start site of the human CCK-AR gene. Two sequence changes were detected in the promoter region: a G to T change in nucleotide -128 and an A to G change in nucleotide -81 (GenBank database under accession number D85606). The frequencies of the genotypes and haplotypes of these two polymorphisms were compared in 109 Japanese patients with PD and 400 age- and gender-matched normal Japanese control subjects. The frequency of variant genotypes (-81A/G, -128G/T; G/G, G/T, and G/G, T/T) having variant haplotype (-81G/-128T) was significantly higher in PD than in controls (P < 0.0001, OR = 2.81, 95% CI = 1.74-4.39). The statistical differences between the haplotype distributions in the PD and control groups were highly significant: the frequency of variant haplotype (-81G/-128T) was higher in the former group than in the latter (P < 0.0001). This association was not affected by clinical characteristics such as age, gender, and age at onset of PD. In this study, the first to report the positive association of the CCK-AR polymorphisms and PD, haplotype analyses further strengthened the association based on our comparison of genotype distributions. The CCK-AR gene polymorphism may be involved in the neurobiology of PD. [Abstract]

Wang Z, Valdes J, Noyes R, Zoega T, Crowe RR.
Possible association of a cholecystokinin promotor polymorphism (CCK-36CT) with panic disorder.
Am J Med Genet 1998 May 8;81(3):228-34
"We searched for mutations in the CCK gene in panic disorder with single-strand conformational polymorphism (SSCP) analysis of the three exons and promotor region of the gene. We found a C-->T transition at position -36 (CCK(-36C-->T)) in a GC box, a binding site for transcription factor Sp1, in the promotor region. The allele frequency was 0.168 (95% CI, 0.116-0.221) in 98 persons with panic disorder and 0.083 (95% CI, 0.059-0.107) in 247 geographically matched, unscreened controls. A transmission disequilibrium test based on panic disorder as the affected phenotype was nonsignificant (chi2 = 0.93), but when panic disorder or attacks were considered as affected, statistically significant transmission disequilibrium was detected (chi2 = 4.00, P < 0.05). Linkage analysis was uninformative. In exploratory analyses to search for clinical correlations, the "T" allele was found in 59% of 22 persons with panic attacks but not panic disorder, compared with 31% of those who met the criteria for panic disorder. An association between the CCK polymorphism and panic disorder cannot be considered established due to the inconsistencies in the results noted above, but if the provisional association can be replicated, the findings are consistent with CCK(-36C-->T) being a disease-susceptibility allele that alone is neither necessary nor sufficient to cause panic disorder but that increases vulnerability by acting epistatically." [Abstract]

Hattori E, Yamada K, Toyota T, Yoshitsugu K, Toru M, Shibuya H, Yoshikawa T.
Association studies of the CT repeat polymorphism in the 5' upstream region of the cholecystokinin B receptor gene with panic disorder and schizophrenia in Japanese subjects.
Am J Med Genet 2001 Dec 8;105(8):779-82
"The tetrapeptide of cholecystokinin (CCK), CCK-4, is known to induce panic attacks in human subjects, while CCK-8 is reported to have a therapeutic effect on schizophrenia symptoms. Recently, we have identified a novel microsatellite polymorphism in the 5' upstream region of the CCK gene and shown a significant association between this polymorphism and panic disorder. In this study, we have investigated the CCK-B receptor (CCKBR) gene, which is the main constituent of the CCK receptor in the CNS. Recently, a dinucleotide repeat, (CT)(n), in the 5' regulatory region of the CCKBR gene was reported to be associated with panic disorder in Canadian samples. To evaluate an association of the CT repeat with panic disorder and schizophrenia, we genotyped 71 subjects with panic disorder, 154 schizophrenics and 199 controls. However, no evidence of allelic association was found between the polymorphic repeat of the CCKBR gene and either panic disorder or schizophrenia (P = 0.186 and 0.987, respectively). Together with the negative reports on association analyses using other polymorphisms of the CCKBR gene and Japanese samples, the present results exclude a major genetic contribution of the CCKBR gene to susceptibilities to panic disorder and schizophrenia in Japanese cohorts." [Abstract]

Hösing VG, Schirmacher A, Kuhlenbäumer G, Freitag C, Sand P, Schlesiger C, Jacob C, Fritze J, Franke P, Rietschel M, Garritsen H, Nöthen MM, Fimmers R, Stögbauer F, Deckert J
Cholecystokinin- and cholecystokinin-B-receptor gene polymorphisms in panic disorder.
J Neural Transm Suppl. 2004;(68):147-56.
Panic disorder like other neuropsychiatric disorders is believed to be caused by multiple psychosocial and biological factors. Several lines of evidence point to a role for the peptide neurotransmitter cholecystokinin in the pathogenesis of panic disorder. We therefore determined the allele and genotype frequencies of a single nucleotide polymorphism in the CCK gene (-36C>T) and one CT repeat polymorphism in the CCK-B-receptor gene in a German panic disorder sample (n = 115 for CCK gene polymorphism, n = 111 for CCK-B-receptor polymorphism) and compared them with gender and age matched controls. The length of the polymorphic CT repeat alleles varies between 146 bp and 180 bp. We first analysed the results by a permutation test which provided evidence for heterogeneity between patients and controls (p=0.002). We then analysed the data as a di-allelic polymorphism with a short (146-162bp) and a long (164-180bp) allele and as a tetra-allelic polymorphism with 4 alleles (146-154bp, 156-162bp, 164-170bp, 172-180bp). In the di-allelic analysis as well as in the tetra-allelic analysis there was an excess of the longer allele (p = 0.001) or the two longer alleles (p = 0.041) respectively in patients with panic disorder. No difference between groups was observed for the -36C > T polymorphism. Our findings are consistent with the notion that genetic variation in the CCK neurotransmitter system contributes to the pathogenesis of panic disorder. [Abstract]

Hansen TV, Rehfeld JF, Nielsen FC.
Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter.
Mol Psychiatry 2000 Jul;5(4):443-7
"Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and in man significant quantities are expressed in all regions of the brain.1,2 Therefore, CCK has been implicated in a variety of CNS functions-such as feeding behavior, anxiety, analgesia and memory functions as well as psychiatric disease like panic disorder and schizophrenia (for review, see2,3). Recently, a number of studies have indicated that a C-36 to T transition in the CCK gene promoter Sp1 element4 (Figure 1) is associated with alcoholism and withdrawal symptoms as well as panic disorder.5-7 Moreover, it has been proposed that the polymorphism plays a direct role in the pathogenesis of the disorders by decreasing the expression and synthesis of CCK peptides. The significance of these findings is still unclear and other studies have failed to demonstrate linkage between the polymorphism and alcoholism.8 In this study we examined the function of the C-36 to T transition in transcription of the human CCK gene. We demonstrate that substitution of the C-36 residue causes a slight reduction of Sp1 and Sp3 binding, but this has no effect on transcription in vivo. Moreover, no difference in the response to physiological stimuli was observed. Taken together the results show that the C to T polymorphism does not play a direct role in the pathogenesis of either alcoholism or panic disorder and that a putative association to these disorders is likely to be the result of co-segregation with a linked mutation." [Abstract]

Hamilton SP, Slager SL, Helleby L, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA.
No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder.
Mol Psychiatry 2001 Jan;6(1):59-65
"Growing animal data implicate cholecystokinin in the regulation of anxiety, while human clinical research confirms the role of cholecystokinin in the provocation of panic attacks. Antipanic medications suppress the ability of cholecystokinin to induce panic attacks, and may alter the expression of the cholecystokinin gene. Thus, there is increased interest in understanding the molecular genetic component of these observations. Recent association studies using persons with panic disorder described some association between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B-receptor and panic disorder. In this study, we used a family-based design, employing 596 individuals in 70 panic disorder pedigrees, as well as 77 haplotype relative risk 'triads'. Subjects were genotyped for two polymorphisms: the polymorphic microsatellite marker in the CCK-BR locus using PCR-based genotyping and at a single nucleotide polymorphism in the CCK promoter using a fluorescence polarization detection assay, and the data were analyzed for genetic association and linkage. Employing a variety of diagnostic and genetic models, linkage analysis produced no significant lod scores at either locus. Family-based tests of association, the haplotype-based haplotype relative risk statistic and the transmission disequilibrium test, were likewise non-significant. The results reported here provide little support for the role of these polymorphisms in panic disorder." [Abstract]

Ise K, Akiyoshi J, Horinouchi Y, Tsutsumi T, Isogawa K, Nagayama H.
Association between the CCK-A receptor gene and panic disorder.
Am J Med Genet 2003 Apr 1;118B(1):29-31
"Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in the brain. CCK appears to play an important role in the neurobiology of anxiety and panic disorders (PD) in both humans and animals. Recently, we reported that lack of CCKAR had a significant anxiogenic-like effect in rats. In this study, to investigate the role of CCKAR in PD, we compared the CCKAR gene in PD patients and normal controls. Subjects who fulfilled the DSM-IV criteria for PD were 17 males and 26 females. The sequence containing the Pst I polymorphic site in the boundary between intron 1 and exon 2 of the CCKAR gene was studied. Pst I digestion of the PCR products gave two individual alleles: A1 and A2. The A1 allele was the undigested fragment and the A2 allele was the digested one with two variant bands at 264 and 180 bp. Genotypic frequencies were 20.9% (A1-A1), 55.8% (A1-A2), and 41.7% (A2-A2) in patients, and 20.5% (A1-A1), 46.2% (A1-A2), and 33.3% (A2-A2) in controls. Allelic frequencies were 48.8% (A1) and 51.2% (A2) in patients, and 43.6% (A1) and 56.4% (A2) in controls. The chi-square test did not show a significant difference in either genotypic or allelic frequencies between patients and control subjects. The Pst polymorphism of CCKAR may not be associated with PD." [Abstract]

Kato T, Wang ZW, Zoega T, Crowe RR.
Missense mutation of the cholecystokinin B receptor gene: lack of association with panic disorder.
Am J Med Genet 1996 Jul 26;67(4):401-5
"Cholecystokinin tetrapeptide (CCK4) is known to induce panic attacks in patients with panic disorder at a lower dose than in normal controls. Therefore, the cholecystokinin B (CCKB) receptor gene is a candidate gene for panic disorder. We searched for mutations in the CCKB gene in 22 probands of panic disorder pedigrees, using single-strand conformation polymorphism (SSCP) analysis. Two polymorphisms were detected. A polymorphism in an intron (2491 C-->A) between exons 4 and 5 was observed in 10 of 22 probands. A missense mutation in the extracellular loop of exon 2 (1550 G-->A, Val125-->Ile) was found in only one proband. This mutation was also examined in additional 34 unrelated patients with panic disorder and 112 controls. The prevalence rate of this mutation was 8.8% in patients with panic disorder (3/34) and 4.4% in controls (5/112). The mutation did not segregate with panic disorder in two families where this could be tested. These results suggest no pathophysiological significance of this mutation in panic disorder." [Abstract]

Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, Yu BH
The association between panic disorder and the L/L genotype of catechol-O-methyltransferase.
J Psychiatr Res. 2004 Jul-Aug;38(4):365-70.
To clarify the role of catechol-O-methyltransferase (COMT) polymorphism in panic disorder (PD), we investigated a large group of Korean PD patients (N = 178) and controls (N = 182) using a case-control study. We also assessed the response to paroxetine treatment and other clinical variables in the PD patients. The increase in the COMT(L) allele was not statistically significant in PD (p = 0.104). However, compared with the sum of the other genotypes, the frequency of the L/L genotype was significantly higher in PD (p = 0.042). The odd ratios (ORs) also indicated a significant effect of the homozygosity for the COMT(L) allele on an increased risk for PD (OR=2.38; 95% CI 1.03-5.51). In addition, patients with L/L genotype had higher trait-anxiety levels (p = 0.030) and poorer treatment response to paroxetine than those with other genotypes (p = 0.002). Our results suggest that the COMT L/L genotype is associated with PD and the genetic variant of the COMT enzyme may be related to the clinical severity and treatment response to paroxetine in PD. [Abstract]

Woo JM, Yoon KS, Yu BH.
Catechol O-methyltransferase genetic polymorphism in panic disorder.
Am J Psychiatry 2002 Oct;159(10):1785-7
"OBJECTIVE: The authors examined the distribution of catechol O-methyltransferase (COMT) genotypes in patients with panic disorder as well as the relationship between a COMT polymorphism and the clinical characteristics of these patients. METHOD: Fifty-one patients with panic disorder and 45 healthy comparison subjects were tested for a genetic polymorphism of COMT. Clinical variables were assessed for the patients with panic disorder. RESULTS: The frequency of the L/L genotype was significantly higher in the patients with panic disorder than in the healthy subjects (19.6% versus 2.2%). Panic disorder was significantly associated with the L allele and L/L genotype. Patients with panic disorder who had the L/L genotype showed poorer treatment response than those with other genotypes. CONCLUSIONS: These results suggest that the L/L genotype of the COMT gene may be related to the development and treatment outcome of panic disorder in some patients." [Abstract]

Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA.
Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22.
Biol Psychiatry 2002 Apr 1;51(7):591-601
"BACKGROUND: A well-characterized single nucleotide polymorphism (472G/A-Val/Met-SNP8) in the coding sequence of the catechol-O-methyltransferase (COMT) gene leads to a three- to fourfold difference in enzymatic activity and clinical and animal studies suggest a role in anxiety states like panic disorder. METHODS: Subjects from 70 panic disorder pedigrees, and 83 "triads", were genotyped at seven single nucleotide polymorphisms (SNPs), polymorphic microsatellites in the first intron of COMT and approximately 339kb upstream of COMT (D22S944) and analyzed for genetic association and linkage. RESULTS: Linkage analysis showed elevated LOD scores for 472G/A (SNP 8), silent exon 3 substitution (186C/T-SNP 5), and the marker D22S944 (2.88, 2.62, and 2.93, respectively), using a variety of diagnostic and genetic models. Association tests were not significant for the SNPs, but were highly significant for D22S944 (p =.0001-.0003). One three-marker haplotype formed from the above three polymorphisms was significantly associated with panic disorder (p =.0001), as was the "global" p value for this combination (p =.005). In addition, numerous haplotypes with combinations of D22S944 and COMT SNPs were found to be significantly associated with panic disorder. CONCLUSIONS: Our findings provide strong evidence for a susceptibility locus for panic disorder either within the COMT gene or in a nearby region of chromosome 22." [Abstract]

Rothe C, Koszycki D, Bradwejn J, King N, Deluca V, Tharmalingam S, Macciardi F, Deckert J, Kennedy JL
Association of the Val158Met Catechol O-Methyltransferase Genetic Polymorphism with Panic Disorder.
Neuropsychopharmacology. 2006 Mar 8;
Genetic as well as clinical data suggest that catechol O-methyltransferase (COMT) is involved in multiple complex psychiatric conditions. Recent studies have described an association between the Val158Met COMT polymorphism and panic disorder. Other recent investigations provide evidence that there are other loci within or nearby the COMT gene that may contribute to the susceptibility to panic disorder. To further evaluate the influence of the Val158Met COMT polymorphism in panic disorder we genotyped this marker in the coding region of the COMT gene and two additional variants (rs737865 and rs165599) in the 5' and the 3' region, respectively, in two independent Canadian samples: 121 nuclear families, and 89 cases with matched controls. In the nuclear families, significant transmission disequilibrium for the valine allele was observed between the alleles of the Val158Met COMT polymorphism and panic disorder (p<0.01). A significant excess of the valine allele was found in analysis of the case-control sample (p<0.01). This effect was mainly derived from the subgroup of females. This finding, including the female effect, replicates earlier results in studies of the Val158Met polymorphism in panic disorder. No significant results were found for the other two markers. These results support the hypothesis that the valine allele of the Val158Met COMT polymorphism or a nearby locus is involved in the etiopathogenesis of panic disorder. [Abstract]

Olsson CA, Anney RJ, Lotfi-Miri M, Byrnes GB, Williamson R, Patton GC
Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health.
Psychiatr Genet. 2005 Jun;15(2):109-15.
OBJECTIVES: Catechol-O-methyltransferase plays a central role in the metabolism of biogenic amines such as norepinephrine, dopamine and serotonin. Functional studies have demonstrated a dose relationship between ValMet genotypes and catechol-O-methyltransferase activity. Compared with the ValVal genotype, the ValMet and MetMet genotypes result in two- and four-fold reductions in catechol-O-methyltransferase activity, respectively. Two recent reports have observed the association between the MetMet genotype and risk of anxiety in adult populations. We examined the association between the ValMet genotypes and propensity to anxiety across adolescence. METHODS: Participants were drawn from an eight-wave study of the mental and behavioural health of over 2000 young Australians followed from 14 to 24 years of age (Victorian Adolescent Health Cohort Study, 1992 to present). DNA was received from 962 participants using a cheek swab collection method. RESULTS: The odds of reporting persistent episodic anxiety (phobic avoidance, panic attacks) were doubled among carriers of the MetMet genotype (odds ratio 2.0, 95% confidence interval 1.1-3.4, P=0.014). A dose relationship between additional copies of the Met allele and persistent episodic anxiety was also observed (1.5, 1.1-1.94, P=0.007). Stratification by sex showed that the risk effect of the Met allele was among females only. No association was observed for measures of neuroticism, persistent generalized anxiety, or a composite measure of psychiatric distress. CONCLUSION: These data replicate previous findings suggesting association between the ValMet polymorphism and specific expressions of anxiety among females. [Abstract]

Domschke K, Freitag CM, Kuhlenbäumer G, Schirmacher A, Sand P, Nyhuis P, Jacob C, Fritze J, Franke P, Rietschel M, Garritsen HS, Fimmers R, Nöthen MM, Lesch KP, Stögbauer F, Deckert J
Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women.
Int J Neuropsychopharmacol. 2004 Jun;7(2):183-8.
Panic disorder is an anxiety disorder with an estimated heritability of up to 48%. Pharmacological and genetic studies suggest that genes coding for proteins involved in the catecholaminergic system might be relevant for the pathogenesis of the disease. In the present study, we genotyped a single nucleotide polymorphism (472G/A=V158M) in the coding region of the catechol-O-methyl-transferase (COMT) gene in 115 patients with panic disorder and age- and sex-matched controls. Association analysis revealed a significant excess of the more active COMT allele (472G=V158) in patients with panic disorder (p=0.04), particularly in female patients (p=0.01), but not in male patients (p=1.0). The assessment of a possible interaction of the COMT polymorphism with a previously reported functional 30-bp VNTR in the monoamine oxidase A promoter (MAOALPR) in female patients did not yield significant results. Our data support a role of the 472G/A (V158M) COMT polymorphism or a nearby locus in the pathogenesis of panic disorder in women. [Abstract]

Rotondo A, Mazzanti C, Dell'Osso L, Rucci P, Sullivan P, Bouanani S, Gonnelli C, Goldman D, Cassano GB.
Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder.
Am J Psychiatry 2002 Jan;159(1):23-9
"OBJECTIVE: Genetic epidemiologic and clinical data suggest that comorbid panic disorder may define a subtype of bipolar disorder. Comorbid panic disorder might thereby influence the strength of association between bipolar disorder and genes that have been implicated in bipolar disorder on the basis of their function in monoamine neurotransmission and previously reported linkage results. Polymorphic markers at catechol O-methyltransferase (COMT), serotonin transporter (5-HTT), and tryptophan hydroxylase (TPH) genes were analyzed in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. METHOD: Unrelated subjects of Italian descent meeting DSM-III-R criteria for lifetime bipolar disorder (N=111), with (N=49) or without (N=62) comorbid lifetime panic disorder, were compared to 127 healthy subjects. DNA was extracted from blood leukocytes. The frequencies of COMT Val158Met, 5-HTTLPR, and TPH IVS7+218C>A polymorphisms were determined. Genotype and allele frequency comparisons between affected (bipolar disorder, bipolar disorder without panic disorder, or bipolar disorder with panic disorder) and unaffected individuals were carried out with chi-square tests or Fisher's exact tests. RESULTS: Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT Met158 and the short 5-HTTLPR alleles and genotypes. The differences in the frequencies of the TPH IVS7+218A alleles and genotypes approached statistical significance. CONCLUSIONS: The findings support the hypothesis that comorbid panic disorder identifies a genetic subtype of bipolar disorder and suggest a role for COMT and 5-HTT in vulnerability to these disorders." [Abstract]

Leygraf A, Hohoff C, Freitag C, Willis-Owen SA, Krakowitzky P, Fritze J, Franke P, Bandelow B, Fimmers R, Flint J, Deckert J
Rgs 2 gene polymorphisms as modulators of anxiety in humans?
J Neural Transm. 2006 Jun 1;
Rgs2 (regulator of G-protein signalling 2) gene recently was reported as a quantitative trait gene for anxious behaviour in mice and male Rgs2 knockout mice have been shown to be more anxious than wildtype mice. Therefore we investigated four non-coding single nucleotide polymorphisms in a sample of 173 patients with panic disorder and 173 matched controls of German descent. At the genotype level all four SNPs were associated with panic disorder (p = 0.02-0.05). At the haplotype level the strongest association was observed for a haplotype containing SNP3 and SNP 4 (subgroup men and men with agoraphobia: p = 0.01 and 0.03). This points towards a functional polymorphism at the 3' end of the gene. Our results support the hypothesis that variations of the Rgs2 gene play a role also for the development of anxiety in humans. [Abstract]

Ho HP, Westberg L, Annerbrink K, Olsson M, Melke J, Nilsson S, Baghaei F, Rosmond R, Holm G, Björntorp P, Andersch S, Allgulander C, Eriksson E
Association between a functional polymorphism in the progesterone receptor gene and panic disorder in women.
Psychoneuroendocrinology. 2004 Oct;29(9):1138-41.
Although genetic factors are known to be important risk factors for panic disorder there is as yet no conclusive data regarding specific gene variants. Prompted by evidence supporting progesterone to influence the pathophysiology of panic disorder, polymorphisms in the progesterone receptor gene, a single nucleotide polymorphism (G331A) and an insertion/deletion polymorphism (PROGINS) were investigated in 72 patients with panic disorder and 452 controls. The frequency of the A-allele of the G331A polymorphism was higher in panic disorder patients than in controls (p = 0.01). When male and female patients were analyzed separately, the association was observed in female patients only (p = 0.0009), with an odds ratio of 3.5. No differences between groups were observed for the PROGINS polymorphism. In conclusion, these data suggest that the G331A polymorphism in the progesterone receptor gene may influence the risk for panic disorder in women. [Abstract]

Philibert RA, Nelson JJ, Sandhu HK, Crowe RR, Coryell WH.
Association of an exonic LDHA polymorphism with altered respiratory response in probands at high risk for panic disorder.
Am J Med Genet 2003 Feb 15;117B(1):11-7
"Panic disorder (PD) is a clinical syndrome characterized by recurrent discrete episodes of fear accompanied by a variety of physiological and psychological symptoms, often with prominent respiratory components. A series of clinical observations has led some investigators to hypothesize that subtle alterations in ventilatory regulation are integral to at least a subtype of PD. In order to identify genetic factors that might predispose individuals to these alterations in ventilatory response, we conducted single stranded conformation polymorphism analysis across the exons of the lactate dehydrogenase A and B genes (LDHA and LDHB) using DNA prepared from 86 subjects previously characterized by respiratory response to a CO(2) challenge with a variable genetic loading for PD. Remarkably, a single conserved LDHA exon 5 haplotype conferred increased risk for a paradoxical ventilatory response pattern to CO(2) inhalation which robustly separated well subjects at high risk for PD from low-risk control subjects. But, comparison of LDHA exon 5 genotypes in PD probands (n = 25) to that of random newborn controls (n = 182) did not demonstrate any significant differences. Given the pivotal role of LDH in the metabolism of lactate, a known inducer of panic attacks, and the dependence of LDH activity on cell pH, we suggest that LDHA polymorphisms may contribute to the variability to CO(2) respiratory challenge." [Abstract]

Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes R Jr.
Genomewide survey of panic disorder.
Am J Med Genet 2001 Jan 8;105(1):105-9
"We completed a genome scan of 23 multiplex families of panic disorder. Ninety family members had DSM-III-R panic disorder, and another 23 had recurrent, spontaneous panic attacks that did not satisfy these criteria. We typed 469 markers from the CHLC map (ver 8c7) with an average intermarker distance of 10.3 cM. Two-point lod scores were calculated with both a dominant and a recessive model, and maps of lod scores < -2.00, assuming genetic homogeneity, were constructed by using DSM-III-R panic disorder as the affected phenotype. Lod scores were < -2.00 over 94-95% of the genome. The greatest lod score was 2.23 (theta = 0.15) at the D7S2846 locus, located at 57.8 cM on chromosome 7 according to the Marshfield Clinic map. Flanking markers analyzed in a nonparametric, multipoint analysis using GENEHUNTER resulted in an NPL score of 2.97 at 63 cM on the Marshfield map. This region lies within 15 cM from the D7S435 locus, where Knowles et al. [1998] obtained a lod score of 1.71 (theta = 0.10) for panic disorder (now 2.45 with the addition of new families; James Knowles, personal communication). Thus, the maximum evidence of linkage from two genome scans of panic disorder lies within a small region of chromosome 7p." [Abstract]

Hamilton SP, Fyer AJ, Durner M, Heiman GA, Baisre de Leon A, Hodge SE, Knowles JA, Weissman MM.
Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q.
Proc Natl Acad Sci U S A 2003 Mar 4;100(5):2550-5
"Substantial evidence supports that there is a genetic component to panic disorder (PD). Until recently, attempts at localizing genes for PD by using standard phenotypic data have not proven successful. Previous work suggests that a potential subtype of PD called the panic syndrome exists, and it is characterized by a number of medical conditions, most notably bladder/renal disorders. In the current study, a genome scan with 384 microsatellite markers was performed on 587 individuals in 60 multiplex pedigrees segregating PD and bladder/kidney conditions. Using both single-locus and multipoint analytic methods, we found significant linkage on chromosome 22 (maximum heterogeneity logarithm of odds score = 4.11 at D22S445) and on chromosome 13q (heterogeneity logarithm of odds score = 3.57 at D13S793) under a dominant-genetic model and a broad phenotypic definition. Multipoint analyses did not support the observation on chromosome 22. The chromosome 13 findings were corroborated by multipoint findings, and extend our previous findings from 19 of the 60 families. Several other regions showed elevated scores by using when one analytic method was used, but not the other. These results suggest that there are genes on chromosome 13q, and possibly on chromosome 22 as well, that influence the susceptibility toward a pleiotropic syndrome that includes PD, bladder problems, severe headaches, mitral valve prolapse, and thyroid conditions." [Abstract]

Smoller JW, Acierno JS Jr, Rosenbaum JF, Biederman J, Pollack MH, Meminger S, Pava JA, Chadwick LH, White C, Bulzacchelli M, Slaugenhaupt SA.
Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions.
Am J Med Genet 2001 Mar 8;105(2):195-206
"Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene-mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)-mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype ("D-type") designed to capture early-onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety-proneness (D-type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D-type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene-mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder." [Abstract]

MacKinnon DF, Xu J, McMahon FJ, Simpson SG, Stine OC, McInnis MG, DePaulo JR.
Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data.
Am J Psychiatry 1998 Jun;155(6):829-31
"OBJECTIVE: The authors performed an analysis of their published chromosome 18 linkage data on 28 families in which there was bipolar disorder to test the potential of comorbid panic disorder to define a genetic subtype of bipolar disorder. METHOD: Families ascertained through probands with bipolar I disorder were stratified into three groups based on a history of panic disorder, panic attacks, or no panic attacks in the probands. Multipoint nonparametric linkage analysis was performed on data from bipolar I and II family members in each group. RESULTS: Linkage scores for five consecutive 18q marker loci were highest in the families of the probands with panic disorder and lowest for the families of the probands without panic attacks. CONCLUSIONS: This study supports the authors' previously reported clinical hypothesis of a genetic subtype of bipolar disorder identified by comorbid panic disorder. The hypothesis merits prospective testing." [Abstract]

Politi P, Minoretti P, Falcone C, Martinelli V, Emanuele E
Association analysis of the functional Ala111Glu polymorphism of the glyoxalase I gene in panic disorder.
Neurosci Lett. 2006 Mar 27;396(2):163-6.
The zinc metalloenzyme glyoxalase I (GLO1) is thought to play a role in anxiety disorders because a reduced brain expression of GLO1 has been associated with increased anxiety-behaviours in mice. Recently, a functional Ala111Glu polymorphism in GLO1 has been shown to result in a reduced enzyme activity. The present study tested the hypothesis that this common genetic variant could confer susceptibility to panic disorder using an Italian population sample of 162 panic disorder patients and 288 matched controls. Statistical analysis failed to show association with the overall diagnosis of the disease. However, a weak but significant association was demonstrated between this polymorphism and panic disorder without agoraphobia. While our data suggest that this polymorphism is unlikely to have a major function in the pathogenesis of panic disorder, it could play a role in the subgroup of patients without agoraphobic avoidance. [Abstract]

Schumacher J, Abou Jamra R, Becker T, Klopp N, Franke P, Jacob C, Sand P, Fritze J, Ohlraun S, Schulze TG, Rietschel M, Illig T, Propping P, Cichon S, Deckert J, Nöthen MM
Investigation of the DAOA/G30 locus in panic disorder.
Mol Psychiatry. 2005 May;10(5):428-9. [Abstract]

Yamada K, Hattori E, Shimizu M, Sugaya A, Shibuya H, Yoshikawa T.
Association studies of the cholecystokinin B receptor and A2a adenosine receptor genes in panic disorder.
J Neural Transm 2001;108(7):837-48
"Several lines of evidence implicate the cholecystokinin B receptor (CCKBR) and the A2a adenosine receptor (A2aAR) in the etiology of panic disorder. To determine the roles each of these receptors may play in panic disorder, we have performed a mutation screen on the CCKBR gene using single strand conformation polymorphism (SSCP) analysis and sequencing. We identified two novel but rare substitutions in the same allele, [3263G>C; 3264A>G], located in the 3'-untranslated region of the CCKBR gene. We then analyzed 91 unrelated patients and 100 matched controls for the four confirmed polymorphic sites in the CCKBR gene and the 1083C>T polymorphism in the A2aAR gene. No evidence of association between the described variants and panic disorder was found. Our data therefore suggests that the CCKBR and A2aAR genes do not play major roles in the development of this disease." [Abstract]

Lam P, Hong CJ, Tsai SJ
Association study of A2a adenosine receptor genetic polymorphism in panic disorder.
Neurosci Lett. 2005 Apr 18;378(2):98-101.
The adenosine A2a receptor (A2aAR) is thought to be implicated in the pathogenesis of panic disorder because caffeine, a potent antagonist for A2aAR, can precipitate panic attacks, and because disruption of the A2aAR gene increased anxiety-behaviors in mice. Recent studies demonstrated that the A2aAR 1976T > C genetic variant confers susceptibility to panic disorder though not by all studies. The present study tested the hypothesis that the A2aAR 1976T > C genetic variant confers susceptibility to panic disorder using a Chinese population of 104 panic disorder patients and 192 normal controls. We also tested whether the A2aAR 1976T > C polymorphism relates to the age of onset or subtype of panic disorders. Neither the distribution of the A2aAR 1976T > C genotypes (P = 0.296) or alleles (P = 0.864), nor the age of onset (P = 0.719) were significantly different among genotype groups. Furthermore, no association was demonstrated between this A2aAR polymorphism and either mitral-valve prolapse or agoraphobia in panic-disorder patients. These findings suggested that it is unlikely that the A2aAR 1976T > C polymorphism plays a major role in panic disorder pathogenesis in the Chinese population. The positive association between this polymorphism and panic disorder found in western population but not in Asian population suggests that this association could be ethnicity-dependent. The 1976C > T polymorphism may be in linkage disequilibrium with a functional variant that affects panic disorder, and the extent of this linkage disequilibrium is not similar for all ethnic populations. [Abstract]

Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA
Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder.
Neuropsychopharmacology. 2004 Mar;29(3):558-65.
Data from clinical and behavioral pharmacological studies have implicated adenosine in anxiety behaviors, while genetic studies have suggested that adenosine receptors may be associated with panic disorder. We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pedigrees. Individuals from 70 panic disorder pedigrees, and 83 child-parent 'trios', were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association. Linkage analysis revealed elevated LOD scores for a silent substitution (1083C/T, SNP-4) in the second coding exon. This SNP has been previously reported to be associated with panic disorder. We observed a maximal heterogeneity LOD score of 2.98 (theta=0) under a recessive genetic model and narrow diagnostic model. Other SNPs showed no evidence for linkage. Association tests were not significant for any of the five ADORA2A SNPs. When SNP haplotypes were assessed in the triads with TRANSMIT, one 3-marker haplotype (SNPs 1, 4, 5) was nominally significantly associated with panic disorder (p=0.029). Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus. Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A. Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder. [Abstract]

Deckert J, Nothen MM, Franke P, Delmo C, Fritze J, Knapp M, Maier W, Beckmann H, Propping P.
Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease.
Mol Psychiatry 1998 Jan;3(1):81-5
"Several lines of evidence suggest a contribution of adenosinergic neurotransmission to the development of panic disorder. We therefore hypothesized that variation in the A1 and A2a adenosine receptor (AR) genes modifies genetic susceptibility to panic disorder. To test this hypothesis, we screened 38 patients with panic disorder for mutations in the coding sequence of the A1AR and A2aAR genes. An association study between the identified DNA sequence variants and panic disorder was performed in an extended sample of 89 patients and matched controls. One silent mutation (716T/G) in the A1AR gene and two silent mutations (432C/T and 1083C/T) in the A2aAR gene were detected. The association sample shows a significant association between the 1083T allele (P=0.01) and 1083T/T genotype (P=0.024) of the A2AR gene and panic disorder. Our findings thus lend further support to the hypothesis that the A2aAR gene, or a locus in linkage disequilibrium with it, confers susceptibility to panic disorder. Replication studies in independent samples with nuclear families applying the transmission disequilibrium test (TDT) are warranted." [Abstract]

Olsson M, Annerbrink K, Westberg L, Melke J, Baghaei F, Rosmond R, Holm G, Andersch S, Allgulander C, Eriksson E
Angiotensin-related genes in patients with panic disorder.
Am J Med Genet B Neuropsychiatr Genet. 2004 May 15;127(1):81-4.
Enhanced respiratory variability and decreased heart rate variability have repeatedly been observed in patients with panic disorder. Prompted by the notion that angiotensin may be involved in the control of respiration, heart rate variability, and anxiety-like behavior, we investigated the putative association between polymorphisms in three angiotensin-related genes and panic disorder-angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II (ANG II) receptor type 1 (ATr1) in 72 patients with panic disorder and 504 controls. Allele and genotype distribution of the ATr1 A1166C allele and the AGT M235T did not differ between patients and controls. With respect to the ACE I/D polymorphism, the I allele was found to be more frequent in male (chi(2) = 8.042, df = 1, P = 0.005), but not female, panic disorder patients than in controls. The results of this investigation provide preliminary evidence for the suggestion that angiotensin-related genes may be associated with panic disorder in men. [Abstract]

Shimizu E, Hashimoto K, Kobayashi K, Mitsumori M, Ohgake S, Koizumi H, Okamura N, Koike K, Kumakiri C, Nakazato M, Komatsu N, Iyo M
Lack of association between angiotensin I-converting enzyme insertion/deletion gene functional polymorphism and panic disorder in humans.
Neurosci Lett. 2004 Jun 3;363(1):81-3.
Family and twin studies have indicated that genes influence susceptibility to panic disorder, but the genes involved remain unknown. The neuropeptide angiotensin II has been found to be involved in anxiety and regulation of respiration which are important in the pathophysiology of panic attacks. Assuming that angiotensins may be candidate genes in panic disorder, we analyzed the association between panic disorder and angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) gene functional polymorphism. We recruited 101 patients with panic disorder diagnosed according to DSM-IV criteria, and 184 control subjects in the study. No significant differences in the frequency of the genotype or allele in the polymorphism between patient and control groups were found (genotype, chi(2)=0.56, d.f.=2, P=0.77; allele, chi(2)=0.074, d.f.=1, P=0.78). This study suggests that the ACE I/D gene polymorphism is not directly associated with panic disorder in our Japanese patient group. [Abstract]

Hamilton SP, Slager SL, Mayo D, Heiman GA, Klein DF, Hodge SE, Fyer AJ, Weissman MM, Knowles JA
Investigation of polymorphisms in the CREM gene in panic disorder.
Am J Med Genet B Neuropsychiatr Genet. 2004 Apr 1;126(1):111-5.
Clinical and animal studies suggest a role for pathways regulated by cyclic-AMP in anxiety. Mouse gene deletion studies, our own linkage findings on chromosome 10, and a recently published genetic association study by Domschke et al. [2003: Am J Med Genet 117B:70-78] suggest that the cAMP responsive element modulator (CREM) may be involved in panic disorder. We have employed a family-based design to investigate the role of DNA sequence variations in the gene for CREM in panic disorder. We have genotyped 613 individuals in 70 panic disorder pedigrees, as well as 42 parent/offspring triads. Subjects were genotyped at two informative single nucleotide polymorphisms (SNPs) and three polymorphic microsatellites in the CREM genomic region; and the data were analyzed for genetic association and linkage. Linkage analysis employing several diagnostic/genetic models produced a maximum lod score of 0.63 for SNP-1, located in the 5' UTR of CREM, under a dominant model with a broad diagnostic definition of panic disorder. Non-parametric analysis, using the NPL statistic or FBAT, also did not support any linkage or association between the markers and panic disorder. All five markers (spanning 77 kb) used in the study showed modest, but significant linkage disequilibrium. Analysis of 2-, 3-, 4-, or 5-marker haplotypes using TRANSMIT failed to find any globally significant results; however, individual haplotypes containing a single allele of MS-3 were nominally associated with panic disorder. These findings provide little additional evidence for a susceptibility locus for panic disorder either within the CREM gene or in a nearby region of chromosome 10p11 in our sample. [Abstract]

Lindberg C, Koefoed P, Hansen ES, Bolwig TG, Rehfeld JF, Mellerup E, Jørgensen OS, Kessing LV, Werge T, Haugbøl S, Wang AG, Woldbye DP
No association between the -399 C > T polymorphism of the neuropeptide Y gene and schizophrenia, unipolar depression or panic disorder in a Danish population.
Acta Psychiatr Scand. 2006 Jan;113(1):54-8.
OBJECTIVE: A polymorphism in the promoter region of the NPY gene at position -399 C > T was recently reported to be associated with schizophrenia in a Japanese population and with treatment refractory unipolar depression in a Swedish population. The objective of this study was to investigate potential associations between the polymorphism and three psychiatric disorders in a Danish population. METHOD: We investigated the occurrence of the polymorphism in patients with schizophrenia (n = 291), unipolar depression (n = 256) and panic disorder (n = 142) compared with controls (n = 716). RESULTS: We detected the polymorphism -399 C > T at a frequency of 48% in controls. No significant differences were found between genotype or allele frequencies in controls vs. the patient groups. CONCLUSION: The lack of association between the -399 C > T polymorphism and schizophrenia, unipolar depression or panic disorder, respectively, suggests that the polymorphism is not involved in the etiology of these disorders in the Danish population. [Abstract]

Martínez-Barrondo S, Sáiz PA, Morales B, García-Portilla MP, Coto E, Alvarez V, Bascarán MT, Bousoño M, Bobes J
Negative evidences in association between apolipoprotein E polymorphism and panic disorder.
Eur Psychiatry. 2006 Jan;21(1):59-61.
The aim is to investigate the association between apolipoprotein E (ApoE) and panic disorder (PD). Genotyping 92 PD patients [Diagnostic Statistic Manual IV (DSM IV) criteria] and 174 controls no differences were found between both groups. Variation in the ApoE-gene was not associated with the development of PD. [Abstract]

Shimizu E, Hashimoto K, Koizumi H, Kobayashi K, Itoh K, Mitsumori M, Ohgake S, Okamura N, Koike K, Matsuzawa D, Zhang L, Kumakiri C, Nakazato M, Komatsu N, Iyo M
No association of the brain-derived neurotrophic factor (BDNF) gene polymorphisms with panic disorder.
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jun;29(5):708-12.
Several lines of evidence suggest that genetic factors might contribute to susceptibility to panic disorder. Our previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders and eating disorders. Assuming that BDNF may be implicated in the putative common pathophysiology of depression and anxiety, we analyzed the association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C > T (formerly named C270T) in the noncoding region of exon V and 196G > A (val66met) in the coding region of exon XIIIA, with panic disorder. In this study, 109 patients with panic disorder diagnosed according to the DSM-IV criteria, and 178 control subjects were recruited. There were no significant differences in the frequency of the genotype or allele in these two SNPs between patients and controls [132C > T in exon V: genotype, p = 1.0, allele, p = 0.59; 196G > A (val66met) in exon XIIIA: genotype, p = 0.77, allele, p = 0.78]. Furthermore, no significant associations of agoraphobia with the two SNPs were detected. This study suggests that the BDNF gene polymorphisms are not associated with panic disorder in our Japanese population. [Abstract]

Lam P, Cheng CY, Hong CJ, Tsai SJ
Association study of a brain-derived neurotrophic factor (Val66Met) genetic polymorphism and panic disorder.
Neuropsychobiology. 2004;49(4):178-81.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, plays an important role in the development, maintenance and function of several neuronal systems. Recent studies have demonstrated that antidepressants, commonly used for panic disorder treatment, can increase central BDNF. In addition, animals with BDNF deficits have higher levels of anxiety when exposed to stressors in comparison to normal controls. The present study tested the hypothesis that the BDNF gene Val66Met polymorphism is associated with panic disorder. In this study, therefore, the incidence of this polymorphism was compared in 103 panic disorder patients and 180 normal controls. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing the two groups. Furthermore, no association was demonstrated between this BDNF polymorphism and either mitral valve prolapse or agoraphobia in panic disorder patients. These findings suggest that the investigated BDNF polymorphism does not play a major role in the pathogenesis of panic disorder in this Chinese population. Further studies exploring the relationship between genetic variations of BDNF and the cerebral atrophy associated with, and antidepressant treatment response in, panic disorder may be appropriate. [Abstract]

Hettema JM, Neale MC, Kendler KS.
A review and meta-analysis of the genetic epidemiology of anxiety disorders.
Am J Psychiatry 2001 Oct;158(10):1568-78
"OBJECTIVE: The authors conducted meta-analyses of data from family and twin studies of panic disorder, generalized anxiety disorder, phobias, and obsessive-compulsive disorder (OCD) to explore the roles of genetic and environmental factors in their etiology. METHOD: MEDLINE searches were performed to identify potential primary studies of these disorders. Data from studies that met inclusion criteria were incorporated into meta-analyses that estimated summary statistics of aggregate familial risk and heritability for each disorder. RESULTS: For family studies, odds ratios predicting association of illness in first-degree relatives with affection status of the proband (disorder present or absent) were homogeneous across studies for all disorders. The calculated summary odds ratios ranged from 4 to 6, depending on the disorder. Only for panic disorder and generalized anxiety disorder could the authors identify more than one large-scale twin study for meta-analysis. These yielded heritabilities of 0.43 for panic disorder and 0.32 for generalized anxiety disorder. For panic disorder, the remaining variance in liability could be attributed primarily to nonshared environment. For generalized anxiety disorder, this was true for men, but for women, a potentially significant role for common familial environment was also seen. CONCLUSIONS: Panic disorder, generalized anxiety disorder, phobias, and OCD all have significant familial aggregation. For panic disorder, generalized anxiety disorder, and probably phobias, genes largely explain this familial aggregation; the role of family environment in generalized anxiety disorder is uncertain. The role of nonshared environmental experience is significant, underscoring the importance of identifying putative environmental risk factors that predispose individuals to anxiety." [Abstract]

Gorwood P, Feingold J, Ades J.
[Genetic epidemiology and psychiatry (I): scope and limitations of familial studies. Case of panic disorder]
Encephale 1999 Jan-Feb;25(1):21-9
"Genetics epidemiology shed new light on multifactorial disorders for which genes are partly involved, for example on numerous psychiatric diseases. Nevertheless, each epidemiological technic has it's caracteristics and limitations. This review discuss the impact of aggregation studies, on the bases of an example, namely all aggregation studies on panic disorder. We detected through Medline thirteen studies, comparing 3,700 relatives of 780 probands affected with panic disorder, with 3,400 relatives of 720 unaffected controls. It is computed that relatives of patients with panic disorder have an increased risk (10.7%) for panic disorder than relatives of controls (1.4%), relatives from affected probands having a high relative risk (6.8) for panic disorder according to the meta-analysis. On the basis of these 13 aggregation studies, there is an important attribuable risk (78.3%) of "having a familial history of panic disorder" in the risk for panic disorder. Furthermore, the estimated heritability is 73% (73% of the total variance would be explained by additive genetic effects), if Reich's conditions are fulfilled for a valid estimation of the heritability on the basis of aggregation families. These studies can also be used to highlight the variability of expression according to gender, to show the relevance of quantitative approaches (versus the qualitative approach which is nearly systematically used), to underline the informations raised by experimental technics (such as panic disorder induced by lactate), and to raise the potential existence of phenocopies. Lastly, aggregation studies on panic disorder can help to understand the high comorbidity of this disorder, with other anxiety disorders and mood disorder." [Abstract]

Vieland VJ, Goodman DW, Chapman T, Fyer AJ.
New segregation analysis of panic disorder.
Am J Med Genet 1996 Apr 9;67(2):147-53
"We performed simple segregation analyses of panic disorder using 126 families of probands with DSM-III-R panic disorder who were ascertained for a family study of anxiety disorders at an anxiety disorders research clinic. We present parameter estimates for dominant, recessive, and arbitrary single major locus models without sex effects, as well as for a nongenetic transmission model, and compare these models to each other and to models obtained by other investigators. We rejected the nongenetic transmission model when comparing it to the recessive model. Consistent with some previous reports, we find comparable support for dominant and recessive models, and in both cases estimate nonzero phenocopy rates. The effect of restricting the analysis to families of probands without any lifetime history of comorbid major depression (MDD) was also examined. No notable differences in parameter estimates were found in that subsample, although the power of that analysis was low. Consistency between the findings in our sample and in another independently collected sample suggests the possibility of pooling such samples in the future in order to achieve the necessary power for more complex analyses." [Abstract]

Maron E, Nikopensius T, Kõks S, Altmäe S, Heinaste E, Vabrit K, Tammekivi V, Hallast P, Koido K, Kurg A, Metspalu A, Vasar E, Vasar V, Shlik J
Association study of 90 candidate gene polymorphisms in panic disorder.
Psychiatr Genet. 2005 Mar;15(1):17-24.
OBJECTIVE: In the present investigation we screened a large number of single nucleotide polymorphisms in the genes relevant to the neurobiology of anxiety for their association with panic disorder (PD). METHODS: The study sample included 127 patients with PD and 146 healthy control subjects. Using Arrayed Primer Extension technology we genotyped 90 polymorphisms in 21 candidate genes of serotonin, cholecystokinin, dopamine and opioid neurotransmitter systems. The association and haplotype analyses were performed in the whole group (PD-all) and in the subgroups of PD comorbid with major depression (PD-comorbid, n = 60) and without any comorbidity (PD-pure, n = 42). RESULTS: From the set of 90 polymorphisms, eight single nucleotide polymorphism markers in eight genes displayed at least a nominal association with any of the studied PD phenotype subgroups. Several polymorphisms of cholecystokinin, serotonin and dopamine systems were associated with PD-all and/or PD-comorbid phenotypes, while pure PD was associated only with HTR2A receptor 102T-C (P = 0.01) and DRD1 receptor -94G-A (P = 0.02) polymorphisms. Haplotype analysis supported an association of the cholecystokinin gene TG haplotype with the PD-all group (P = 0.04), whereas DRD1 receptor CAA and HTR2A receptor AT haplotypes were associated with a lower risk for PD-pure phenotype (P = 0.03 and P = 0.04, respectively). CONCLUSIONS: The study results suggest that genetic variants of several candidate genes of neurotransmitter systems, each of a minor individual effect, may contribute to the susceptibility to PD. Our data also indicate that genetic variability may have a distinctive influence on pure and comorbid phenotypes of PD. [Abstract]

Inada Y, Yoneda H, Koh J, Sakai J, Himei A, Kinoshita Y, Akabame K, Hiraoka Y, Sakai T.
Positive association between panic disorder and polymorphism of the serotonin 2A receptor gene.
Psychiatry Res. 2003 May 1;118(1):25-31.
"Family and twin studies have shown that genetic factors play an important role in the etiology of panic disorder. However, linkage and association studies using DNA markers have yielded inconclusive results. Increased serotonin neurotransmission may cause or be related to panic disorder. Assuming that genes regulating the serotonin system are involved in the pathogenesis of panic disorder, the authors searched for a genetic association of panic disorder with the serotonin 1A (HTR1A), 2A (HTR2A), and 2C (HTR2C) receptor genes. HTR1A, HTR2A and HTR2C polymorphisms were detected by the polymerase chain reaction method with analysis of restriction fragment-length polymorphisms (PCR-RFLP). The subjects were 63 biologically unrelated patients with panic disorder and 100 biologically unrelated normal control subjects who were native Japanese living in the western area of Japan. HTR1A and HTR2C showed no significant association with panic disorder. However, the frequency of the MspI A2 allele of HTR2A was significantly higher in the patients than in the normal control subjects. The study showed a positive association between panic disorder and the HTR2A gene, suggesting that HTR2A plays an important role in the pathogenesis of panic disorder." [Abstract]

Fehr C, Schleicher A, Szegedi A, Anghelescu I, Klawe C, Hiemke C, Dahmen N.
Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy.
Prog Neuropsychopharmacol Biol Psychiatry 2001 Jul;25(5):965-82
"1. Alterations in the serotonergic neurotransmission have been frequently described for patients suffering from alcoholism, anxiety disorders and narcolepsy. 2. The authors tested for association of the 5-HT2A receptor polymorphism (T102C) and the intron 7 tryptophan hydroxylase (TPH) polymorphism (A218C) among 176 alcohol dependent patients, 35 patients with panic disorder, 50 patients with generalized anxiety disorder, 55 patients with narcolepsy and 87 healthy controls. 3. Allele and genotype frequencies of the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH polymorphism (A218C) were almost similar between the patients suffering from alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy. 4. There was no association between the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH (A218C) polymorphisms and alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy in our subsets of German patients." [Abstract]

Logue MW, Vieland VJ, Goedken RJ, Crowe RR.
Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7.
Am J Med Genet. 2003 Aug 15;121B(1):95-9.
"This article presents a Bayesian re-analysis of a linkage study of panic disorder Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. In the initial analysis Crowe et al. failed to find compelling evidence for linkage based on either LOD scores or NPL scores anywhere in the genome. The maximum LOD score was 2.23 on chromosome 7 at marker D7S2846 (57.79 cM according to Marshfield). Over the past several years we have been developing a Bayesian alternative approach to linkage analysis, based on direct measurement of the posterior probability of linkage (PPL), and have shown elsewhere that this approach has several advantages over the available alternatives for mapping complex-disease genes Vieland [1998: Am J Med Genet 63:947-954]; Wang et al. [1999: Genet Epidemiol 17(Suppl 1):S749-S754]; Wang et al. [2000: Ann Hum Genet 64:533-553]; and Vieland et al. [2001: Hum Hered 51:199-208]. One limitation of this approach in previous applications has been that it required the investigator to specify a fixed genetic model for the trait. We employ a new implementation of the PPL that treats the unknown trait model as a vector of nuisance parameters, which is integrated out of the PPL equation. When we apply this new model-integrated version of the PPL to the data of Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109] we obtain much clearer evidence than previously reported for a locus on chromosome 7, with an 80% probability of linkage to marker D7S521. A second location is also identified on chromosome 16 near marker D16S749 (PPL = 24%). The results for the remainder of the genome are consistently low. The two loci identified here are also supported by independent evidence from other studies." [Abstract]

Thorgeirsson TE, Oskarsson H, Desnica N, Kostic JP, Stefansson JG, Kolbeinsson H, Lindal E, Gagunashvili N, Frigge ML, Kong A, Stefansson K, Gulcher JR.
Anxiety with panic disorder linked to chromosome 9q in iceland.
Am J Hum Genet 2003 May;72(5):1221-30
"The results of a genomewide scan for genes conferring susceptibility to anxiety disorders in the Icelandic population are described. The aim of the study was to locate genes that predispose to anxiety by utilizing the extensive genealogical records and the relative homogeneity of the Icelandic population. Participants were recruited in two stages: (1) Initial case-identification by a population screening for anxiety disorders, using the Stamm Screening Questionnaire, was followed by aggregation into extended families, with the help of our genealogy database; and (2) those who fulfilled the diagnostic and family aggregation criteria underwent a more detailed diagnostic workup based on the Composite International Diagnostic Interview. Screening for anxiety in close relatives also identified additional affected members within the families. After genotyping was performed with 976 microsatellite markers, affected-only linkage analysis was done, and allele-sharing LOD scores were calculated using the program Allegro. Linkage analysis of 25 extended families, in each of which at least one affected individual had panic disorder (PD), resulted in a LOD score of 4.18 at D9S271, on chromosome 9q31. The intermarker distance was 4.4 cM on average, whereas it was 1.5 cM in the linked region as additional markers were added to increase the information content. The linkage results may be relevant not only to PD but also to anxiety in general, since our linkage study included patients with other forms of anxiety." [Abstract]

Wang AG, Dahl HA, Vang M, Als TD, Ewald H, Kruse TA, Mors O
Genetics of panic disorder on the Faroe Islands: a replication study of chromosome 9 and panic disorder.
Psychiatr Genet. 2006 Jun;16(3):99-104.
OBJECTIVE: The population of the Faroe Islands in the North Atlantic Ocean is likely to have the same ancestry as the Icelandic population. An Icelandic study on Panic Disorder has found some evidence for a loci on chromosome 9. METHODS: On the Faroe Islands we have an ongoing genetic project concerning panic disorder among other psychiatric disorders. We searched for shared alleles and haplotypes in distantly related cases from the isolated and recently found population of the Faroe Islands, using 26 more or less evenly distributed microsatellite markers on chromosome 9, with emphasis on the candidate region identified in the Icelandic study. RESULTS: We have not been able to replicate the Icelandic results. Owing to the study design and sample size, we would not be able to detect areas with small impact. [Abstract]

Domschke K, Kuhlenbaumer G, Schirmacher A, Lorenzi C, Armengol L, DiBella D, Gratacos M, Garritsen HS, Nothen MM, Franke P, Sand P, Fritze J, Perez G, Maier W, Sibrowski W, Estivill X, Bellodi L, Ringelstein EB, Arolt V, Martin-Santos R, Catalano M, Stogbauer F, Deckert J.
Human nuclear transcription factor gene CREM: Genomic organization, mutation screening, and association analysis in panic disorder.
Am J Med Genet 2003 Feb 15;117B(1):70-8
"Panic disorder is an anxiety disorder with an estimated heritability of 48%. Variation in the gene of the nuclear transcription factor "cAMP-responsive element modulator" (CREM) might contribute to its pathogenesis. CREM knock-out mice exhibit significantly less anxiety behavior than wild-type mice and the alternative CREM gene product "inducible cAMP early repressor" (ICER) plays a pivotal role in the hypothalamo-pituitary-adrenal (HPA) axis, which is disturbed in panic disorder. We characterized the genomic organization of the human CREM gene and performed a systematic mutation screening by means of single stranded conformational analysis (SSCA) in a sample of 40 German patients with panic disorder (DSM-III-R). Four novel single nucleotide polymorphisms in CREM promoters P 1 and P 4, one trinucleotide (ATT)-repeat polymorphism in CREM promoter P 2-generating the ICER isoform-and a rare amino acid substitution in CREM exon glut 2 were identified. Association analysis in an extended sample of German patients (n = 88) revealed a significant excess of the shorter CREM P 2 promoter eight-repeat trinucleotide allele and of genotypes containing the eight-repeat trinucleotide allele in panic disorder (P = 0.02), in particular in panic disorder without agoraphobia (P = 0.001). A replication study in independent Italian (n = 76) and Spanish (n = 62) samples, however, failed to confirm this observation. This suggests that the CREM P 2 promoter trinucleotide polymorphism is not a major susceptibility factor in the pathogenesis of panic disorder. Functional analysis of the observed CREM P 2 promoter polymorphism as well as studies in independent panic disorder samples are necessary." [Abstract]

Zhu G, Bartsch O, Skrypnyk C, Rotondo A, Akhtar LA, Harris C, Virkkunen M, Cassano G, Goldman D
Failure to detect DUP25 in lymphoblastoid cells derived from patients with panic disorder and control individuals representing European and American populations.
Eur J Hum Genet. 2004 Jun;12(6):505-8.
Investigation of the co-occurrence of panic and phobic disorders with joint laxity led to the identification of interstitial duplications involving human chromosome 15q24-26 (named 'DUP25') in a Spanish population. DUP25 was observed in 97% of patients and in 7% of control individuals. In the present study, we used two different methods to detect DUP25: high-throughput molecular gene dosage analysis and fluorescence in situ hybridization (FISH). We evaluated 56 lymphoblastoid cell lines derived from 26 unrelated patients with panic disorder obtained from several European and American populations and 30 normal controls. We could not find any cell line showing a result consistent with DUP25. These data do not support any association of DUP25 with panic disorder. [Abstract]

Schumacher J, Otte AC, Becker T, Sun Y, Wienker TF, Wirth B, Franke P, Abou Jamra R, Propping P, Deckert J, Nöthen MM, Cichon S
No evidence for DUP25 in patients with panic disorder using a quantitative real-time PCR approach.
Hum Genet. 2003 Dec;114(1):115-7.
A duplication of chromosome 15q24-q26 (DUP25) has been reported to be associated with anxiety disorders. We tested for the presence of DUP25 in a sample of 50 patients with panic disorder and 50 controls using a quantitative real-time PCR approach. Contrary to the original finding, our results were compatible with the absence of DUP25, and no significant difference could be detected between patients and controls ( P=1.0). Thus, our study does not support the hypothesis of an involvement of DUP25 in panic disorder. [Abstract]

Gratacos M, Nadal M, Martin-Santos R, Pujana MA, Gago J, Peral B, Armengol L, Ponsa I, Miro R, Bulbena A, Estivill X.
A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders.
Cell 2001 Aug 10;106(3):367-79
"Anxiety disorders are complex and common psychiatric illnesses associated with considerable morbidity and social cost. We have studied the molecular basis of the cooccurrence of panic and phobic disorders with joint laxity. We have identified an interstitial duplication of human chromosome 15q24-26 (named DUP25), which is significantly associated with panic/agoraphobia/social phobia/joint laxity in families, and with panic disorder in nonfamilial cases. Mosaicism, different forms of DUP25 within the same family, and absence of segregation of 15q24-26 markers with DUP25 and the psychiatric phenotypes suggest a non-Mendelian mechanism of disease-causing mutation. We propose that DUP25, which is present in 7% control subjects, is a susceptibility factor for a clinical phenotype that includes panic and phobic disorders and joint laxity." [Abstract]

Crowe RR, Wang Z, Noyes R Jr, Albrecht BE, Darlison MG, Bailey ME, Johnson KJ, Zoega T.
Candidate gene study of eight GABAA receptor subunits in panic disorder.
Am J Psychiatry 1997 Aug;154(8):1096-100
"OBJECTIVE: gamma-Aminobutyric acid type A (GABAA) receptor subunit genes are candidate genes for panic disorder. Benzodiazepine agonists acting at this receptor can suppress panic attacks, and both inverse agonists and antagonists can precipitate them. The human GABAA receptor subtypes are composed of various combinations of 13 subunits, each encoded by a unique gene. The authors tested eight of these subunits in a candidate gene linkage study of panic disorder. METHOD: In 21 U.S. and five Icelandic multiplex pedigrees of panic disorder, 104 individuals had DSM-III-R panic disorder (the narrowly defined affected phenotype) and 134 had either this diagnosis or subsyndromal panic disorder characterized by panic attacks that failed to meet either the criterion of attack frequency or the number of criterion symptoms necessary for a definite diagnosis (the broadly defined affected phenotype). The authors conducted lod score linkage analyses with both phenotypes using both a dominant and a recessive model of inheritance for the following loci: GABRA1-GABRA5 (alpha 1-alpha 5), GABRB1 (beta 1), GABRB3 (beta 3), and GABRG2 (gamma 2). RESULTS: The results failed to support the hypothesis that any of these genes cause panic disorder in a majority of the pedigrees. CONCLUSIONS: Within the limitations of the candidate gene linkage method, panic disorder does not appear to be caused by mutation in any of the eight GABAA receptor genes tested." [Abstract]

Nakamura K, Yamada K, Iwayama Y, Toyota T, Furukawa A, Takimoto T, Terayama H, Iwahashi K, Takei N, Minabe Y, Sekine Y, Suzuki K, Iwata Y, Pillai A, Nakamoto Y, Ikeda K, Yoshii M, Fukunishi I, Yoshikawa T, Mori N
Evidence that variation in the peripheral benzodiazepine receptor (PBR) gene influences susceptibility to panic disorder.
Am J Med Genet B Neuropsychiatr Genet. 2006 Apr 5;141(3):222-6.
Panic disorder (PD) is the repeated sudden occurrence of panic attacks, episodes characterized by psychological symptoms. Peripheral benzodiazepine receptor (PBR) is closely associated with personality traits for anxiety tolerance, and that it holds promise as a biological marker of stressful conditions. We have performed association analyses using the polymorphism to determine the PBR in PD. We screened the subjects for sequence variations within the 5' region, the coding region (exons 2-4), and the 3' noncoding region. One novel missense variant in exon 4, derived from the nucleotide transition in codon 162 (CGT --> CAT:485G > A) resulting in an arginine-to-histidine (Arg --> His) change, was detected in these subjects. The 485G > polymorphism of the PBR gene was analyzed in 91 PD patients and 178 controls. The genotypic and allelic analyses of the 485G > A revealed significant differences between the panic patients and the comparison subjects (P = 0.021 and 0.014, respectively). The present study provides new and important evidence that variation in the PBR gene influences susceptibility to PD. [Abstract]

Sand PG, Godau C, Riederer P, Peters C, Franke P, Nothen MM, Stober G, Fritze J, Maier W, Propping P, Lesch KP, Riess O, Sander T, Beckmann H, Deckert J.
Exonic variants of the GABA(B) receptor gene and panic disorder.
Psychiatr Genet 2000 Dec;10(4):191-4
"The enhancement of GABAergic neurotransmission has been closely linked to antipanic drug efficacy. This is the first study to investigate a putative association of exonic sequence variants of the human GABA(B) receptor 1 (GABA(B)R1) gene and susceptibility to panic disorder. Three DNA sequence variants in exons 1a1, 7 and 11 were assessed by polymerase chain reaction-based restriction fragment length polymorphism in a case-control study among patients with panic disorder with and without agoraphobia (DSM III-R criteria) and blood donors. There was no indication of an increased vulnerability to panic disorder or agoraphobia with respect to the allelic variants under study." [Abstract]

Hamilton SP, Haghighi F, Heiman GA, Klein DF, Hodge SE, Fyer AJ, Weissman MM, Knowles JA.
Investigation of dopamine receptor (DRD4) and dopamine transporter (DAT) polymorphisms for genetic linkage or association to panic disorder.
Am J Med Genet 2000 Jun 12;96(3):324-30
"Clinical and animal studies suggest a role for the neurotransmitter dopamine in anxiety states. In humans, one such condition is panic disorder, which is typified by recurrent panic attacks accompanied by anticipatory anxiety. Family, segregation, and twin studies imply a genetic component to the pathophysiology of panic disorder. In this study, we examined the genes for the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) using three common sequence polymorphisms. Two of these polymorphisms were in DRD4, a 12 base-pair insertion/deletion in exon 1 and a 48 base-pair repeat in exon 3, and the third was a 40 base-pair repeat in the 3' untranslated region of DAT. We employed a family-based design, using 622 individuals in 70 families, as well as 82 haplotype relative risk "trios". Subjects were genotyped at the polymorphic loci, and the data were analyzed for genetic association and linkage. There were no significant differences in allele frequencies or occurrence of genotypes within the triads for any of the three polymorphisms. No significant linkage between the DRD4 or DAT polymorphisms and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. However, LOD scores of approximately 1.1 and 1.05 were observed for the DAT and DRD4 exon 1 loci, respectively. The results reported here provide little support for the role of these polymorphisms in panic disorder." [Abstract]

Han L, Nielsen DA, Rosenthal NE, Jefferson K, Kaye W, Murphy D, Altemus M, Humphries J, Cassano G, Rotondo A, Virkkunen M, Linnoila M, Goldman D.
No coding variant of the tryptophan hydroxylase gene detected in seasonal affective disorder, obsessive-compulsive disorder, anorexia nervosa, and alcoholism.
Biol Psychiatry 1999 Mar 1;45(5):615-9
"BACKGROUND: The goal of this study was to evaluate the role of genetic variation in the coding sequence of tryptophan hydroxylase (TPH) in the pathogenesis of several psychiatric diseases in which altered serotonin function has been implicated: bipolar affective disorder (BP), obsessive-compulsive disorder (OCD), anorexia nervosa (AN), seasonal affective disorder (SAD), panic disorder (PD), and alcoholism (Alc). METHODS: Ninety-three percent of the TPH coding sequence was screened by polymerase chain reaction single-strand conformation polymorphism (SSCP) for DNA sequence variations in 128 AN, 88 OCD, 72 SAD, 45 PD, and 36 BP patients and 142 normal volunteers. Also included in the screening were 61 Alc randomly selected from a Finnish alcoholic population in which an association of a TPH intron 7 polymorphism with suicidality was previously observed. Polymorphisms detected by SSCP were characterized by DNA sequencing and by allele-specific restriction enzyme digestion. Genotyping was then performed in 34 Finnish alcoholic suicide attempters. RESULTS: A rare silent mutation was identified in exon 10 and is designated T1095C. The C1095 allele was found in 1 OCD and in 2 AN subjects; all 3 individuals were heterozygous (C1095/T1095) for the variant allele. No association was observed between this TPH T1095C variant with either OCD, AN, Alc, or suicidality. CONCLUSION: These results suggest that the coding sequence of the TPH gene does not contain abundant variants, and may not play a major role in vulnerability to several psychopathologies in which reduced serotonin turnover has been implicated." [Abstract]

Mössner R, Freitag CM, Gutknecht L, Reif A, Tauber R, Franke P, Fritze J, Wagner G, Peikert G, Wenda B, Sand P, Rietschel M, Garritsen H, Jacob C, Lesch KP, Deckert J
The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder.
J Psychopharmacol. 2006 Jul;20(4):547-52.
Panic disorder is a common psychiatric disorder characterized by recurrent anxiety attacks and anticipatory anxiety. Due to the severity of the symptoms of the panic attacks and the frequent additional occurrence of agoraphobia, panic disorder is an often debilitating disease. Elevation of central serotonin levels by drugs such as clomipramine represents one of the most effective treatment options for panic disorder. This points to an important role of dysregulation of the serotonergic system in the genetic etiology of panic disorder. The novel brain-specific 5-HT synthesizing enzyme, tryptophan hydroxylase-2 (TPH2), which represents the rate-limiting enzyme of 5-HT production in the brain, may therefore be of particular importance in panic disorder. We focused on the putative transcriptional control region of TPH2 and identified two novel common single nucleotide polymorphisms (SNPs) of TPH2 in and close to this region. Moreover, a recently described loss-of-function mutation of TPH2 which results in an 80% reduction of serotonin production, was assessed. In an analysis of the putative transcriptional control region SNPs in a sample of panic disorder patients and controls no association of the disorder with the TPH2 SNPs or haplotypes was found. Moreover, the loss-of-function R441H mutation of TPH2 was not present in the panic disorder patients. The results of this first study of TPH2 in panic disorder argue against an importance of allelic variation of TPH2 in the pathogenesis of panic disorder with or without agoraphobia. [Abstract]

Sand PG, Mori T, Godau C, Stober G, Flachenecker P, Franke P, Nothen MM, Fritze J, Maier W, Lesch KP, Riederer P, Beckmann H, Deckert J.
Norepinephrine transporter gene (NET) variants in patients with panic disorder.
Neurosci Lett 2002 Nov 15;333(1):41-4
"Several lines of evidence suggest that catecholamines, especially norepinephrine, are implicated in the etiology and/or symptomatology of panic disorder (PD). At the cellular level, functional noradrenergic neurotransmission depends on synaptic reuptake of norepinephrine as mediated by the norepinephrine transporter (NET). A pharmacological target of agents with an established anti-panic efficacy, e.g. tricyclic antidepressants, the NET is of particular interest in PD. We investigated the NET gene for the presence of 6 naturally occurring exonic sequence variants, 5 of which give rise to amino acid substitutions (Val69Ile, Thr99Ile, Val245Ile, Val449Ile and Gly478Ser) in a population of 87 patients with PD and 89 healthy controls. Except for a silent substitution (G1287A), overall frequencies of variant alleles were low (< or =0.016). None of the variants under study was found to be associated with PD regardless of an additional diagnosis of agoraphobia." [Abstract]

Lee YJ, Hohoff C, Domschke K, Sand P, Kuhlenbäumer G, Schirmacher A, Freitag CM, Meyer J, Stöber G, Franke P, Nöthen MM, Fritze J, Fimmers R, Garritsen HS, Stögbauer F, Deckert J
Norepinephrine transporter (NET) promoter and 5'-UTR polymorphisms: association analysis in panic disorder.
Neurosci Lett. 2005 Mar 22;377(1):40-3.
Several biochemical and pharmacological studies suggest that the catecholaminergic system involving the norepinephrine transporter (NET) is relevant for the pathogenesis of panic disorder. Three single nucleotide polymorphisms in the promoter or untranslated 5' region of the NET gene were investigated by means of RFLP analysis in a sample of 115 German patients with panic disorder and 115 matched controls. Statistical analysis failed to show association with the overall diagnosis of panic disorder. In the subgroup of patients with panic disorder without agoraphobia, however, two polymorphisms were found to be associated with the disease (G/C (rs2397771): p < 0.05; T/C (rs2242446): p < 0.01). While our data do not support a major function of the NET gene in the development of panic disorder, it may play a role in the subgroup of panic disorder without agoraphobia. [Abstract]

Ohara K, Suzuki Y, Ochiai M, Terada H.
Polymorphism in the promoter region of the alpha(2A)-adrenergic receptor gene and panic disorders.
Psychiatry Res 2000 Feb 14;93(1):79-82
"alpha(2)-Adrenergic receptors have been thought to play a crucial role in the etiology or treatment of panic disorders. Polymorphism(s) in the promoter region of the alpha(2) receptor may affect gene expression and be associated with panic disorders. We studied the polymorphism of the alpha(2A) receptor gene at position -1291 reported by Lario et al. (Lario, S., Calls, J., Cases, A., Oriola, J., Torras, A., Rivera, F., 1997. Short repeat on DNA marker at candidate locus. MspI identifies a biallelic polymorphism in the promoter region of the alpha(2A)-adrenergic receptor gene. Clinical Genetics 51, 129-130.) in 114 healthy control subjects and 55 patients with panic disorders. There was no statistically significant difference between controls and patients in either genotype or allele frequency. Our results suggest there is no association between this polymorphism in the promoter region of the alpha(2A) receptor gene and panic disorders." [Abstract]

Wang ZW, Crowe RR, Noyes R Jr.
Adrenergic receptor genes as candidate genes for panic disorder: a linkage study.
Am J Psychiatry 1992 Apr;149(4):470-4
"OBJECTIVE: Several lines of investigation suggest that the noradrenergic neurotransmitter system may be involved in the pathogenesis of panic disorder. Since a mutation in a gene coding for one of the adrenergic receptors could account for both the familial nature and autonomic dysfunction of panic disorder, the authors performed analyses of the linkage between panic disorder and five adrenergic receptor loci. METHOD: The subjects were 14 multiplex pedigrees with DSM-III panic disorder or agoraphobia with panic attacks. The loci tested were the alpha 1/beta 2 pair on chromosome 5q32-q34, the alpha 2/beta 1 pair on chromosome 10q24-q26, and a second alpha 2 locus on chromosome 4. Flanking loci were included in the analysis on chromosomes 5 and 10 to increase the informativeness of the adrenergic receptor loci. RESULTS: Lod scores less than -2.0 were found at all five receptor loci. CONCLUSIONS: These findings provide strong evidence against the possibility that genetic mutation at any of these loci is responsible for panic disorder in these pedigrees." [Abstract]

Steinlein OK, Deckert J, Nothen MM, Franke P, Maier W, Beckmann H, Propping P.
Neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and panic disorder: an association study.
Am J Med Genet 1997 Apr 18;74(2):199-201
"Anxiety disorders have been reported to be associated with low-voltage EEG (LVEEG). Some cases with LVEEG (approximately 1/3) have been linked to chromosome 20q13.2q13.3. In the same chromosomal region, the gene for the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) has been located. We therefore tested the hypothesis that polymorphisms in the CHRNA4 gene show an allelic association with panic disorder. We examined the allele frequencies of three different CHRNA4 polymorphisms in patients with panic disorder and in healthy controls. No significant differences in the allele frequencies of these three polymorphisms were noted. This study does not support an association between panic disorder and the CHRNA4 gene." [Abstract]

Ishiguro H, Arinami T, Yamada K, Otsuka Y, Toru M, Shibuya H.
An association study between a transcriptional polymorphism in the serotonin transporter gene and panic disorder in a Japanese population.
Psychiatry Clin Neurosci 1997 Oct;51(5):333-5
"A polymorphism in the 5' region of the serotonin transporter gene modulates its transcription efficiency. Its short allele has been reported to be associated with neurotic traits. The serotonin transporter is the action site of selective serotonin re-uptake inhibitors, widely used in the treatment of panic disorder. We examined an association between the polymorphism and panic disorder in a case-control study consisting of 66 Japanese patients and 150 controls. The short allele was significantly more frequent in the Japanese than in Caucasians. The patients and the controls had similar allele frequencies, indicating no association between the polymorphism and panic disorder in most Japanese patients." [Abstract]

Hamilton SP, Heiman GA, Haghighi F, Mick S, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA.
Lack of genetic linkage or association between a functional serotonin transporter polymorphism and panic disorder.
Psychiatr Genet 1999 Mar;9(1):1-6
"Given the efficacy of medications that interact with the serotonin transporter (5-HTT) in the treatment of panic disorder, we have used a family-based design to test for genetic association and linkage between panic disorder and a functional polymorphism in the promoter of the gene for 5-HTT. In this study, 340 individuals in 45 families, as well as 74 haplotype relative risk 'trios' were genotyped at the polymorphic locus, which consists of a 44 base pair deletion/insertion. There were no significant differences in allele frequencies or occurrence of genotypes within the triads. No linkage between the 5-HTT polymorphism and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. Recent reports suggest an association between the 5-HTT polymorphism and anxiety-related traits, as measured with personality assessment. The results reported here provide evidence that the genetic basis of panic disorder may be distinct from anxiety-related traits assessed by personality inventories in normal populations." [Abstract]

Deckert J, Catalano M, Heils A, Di Bella D, Friess F, Politi E, Franke P, Nothen MM, Maier W, Bellodi L, Lesch KP.
Functional promoter polymorphism of the human serotonin transporter: lack of association with panic disorder.
Psychiatr Genet 1997 Spring;7(1):45-7
"To probe the hypothesis of a role for a functionally relevant 44 bp insertion/deletion of the serotonin transporter promoter in the aetiopathogenesis of panic disorder, we determined the allele frequency of the variant in two samples (combined n = 158) of panic disorder patients (DSMIII-R) and compared it with its allele frequency in two ethnically matched control samples (combined n = 169). The fact that no difference could be observed (x 2 analysis) argues against a major role for this serotonin transporter promoter polymorphism in the aetiopathogenesis of panic disorder." [Abstract]

Perez M, Brown JS, Vrshek-Schallhorn S, Johnson F, Joiner TE
Differentiation of obsessive-compulsive-, panic-, obsessive-compulsive personality-, and non-disordered individuals by variation in the promoter region of the serotonin transporter gene.
J Anxiety Disord. 2005 Nov 19;
Past research investigating the role of the serotonin transporter gene in OCD has produced mixed findings. One possible reason for the mixed findings is comorbidity. In this study, non-comorbid OCD individuals were compared to non-disordered controls. A sample of panic disordered individuals was also compared to a non-disordered group. Finally, as an exploratory analysis, individuals were assessed for OCPD and their allelic frequencies were also compared to non-disordered individuals. Analyses revealed that there were higher frequencies of the s/s genotype among the OCD group when compared to non-disordered controls. There were no differences in allelic frequencies on the serotonin transporter gene between the panic disordered group, the OCPD group, and the non-disordered control group. This study found that non-comorbid OCD individuals tended to have a higher percentage of the homozygous short genotype than non-disordered individuals. The s/s genotype might serve as a contributory risk factor for OCD. [Abstract]

Olesen OF, Bennike B, Hansen ES, Koefoed P, Woldbye DP, Bolwig TG, Mellerup E
The short/long polymorphism in the serotonin transporter gene promoter is not associated with panic disorder in a Scandinavian sample.
Psychiatr Genet. 2005 Sep;15(3):159. [Abstract]

Martínez-Barrondo S, Saiz PA, Morales B, García-Portilla MP, Coto E, Alvarez V, Bobes J
Serotonin gene polymorphisms in patients with panic disorder.
Actas Esp Psiquiatr. 2005 Jul-Aug;33(4):210-5.
INTRODUCTION: The objective is to investigate the possible association between four serotonin gene polymorphisms (T102C, A-1438G, 5-HTTLPR and VNTR-5HTT) and panic disorder (PD). PATIENTS AND METHOD: 92 PD outpatients (DSM-IV criteria) and 174 healthy volunteers from Asturias (control group) were included. Polymorphisms were determined after polymerase chain reaction amplification followed by digestion with restriction enzymes and electrophoresis on an agarose gel. RESULTS: Both 5-HT2A polymorphisms are in complete linkage disequilibrium in our population. No statistically significant differences in genotype frequencies of serotonin gene polymorphisms (T102C, A-1438G, 5HTTLPR and VNTR-5HTT) were found between patients and control subjects. Allele frequencies did not differ between both groups. No differences were found according to gender. CONCLUSIONS: The polymorphisms studied were not associated with PD in our population. However, larger patient samples are necessary to confirm or reject these findings. [Abstract]

Rothe C, Koszycki D, Bradwejn J, King N, De Luca V, Shaikh S, Franke P, Garritsen H, Fritze J, Deckert J, Kennedy JL
Association study of serotonin-2A receptor gene polymorphism and panic disorder in patients from Canada and Germany.
Neurosci Lett. 2004 Jun 17;363(3):276-9.
The T102C serotonin-2A (5-HT2A) receptor gene polymorphism has been studied extensively in a number of complex psychiatric conditions with mixed results. Recently a genetic association has been described between this polymorphism and panic disorder in a Japanese sample. To evaluate the impact of the T102C polymorphism in panic disorder we genotyped triad families (panic disorder patient and parents), and cases with controls in Canadian and German samples. No significant transmission disequilibrium was observed between the alleles of the T102C 5-HT2A receptor gene polymorphism and panic disorder, nor was a significant excess of either allele found in the case control analysis. Our data suggest thus that this polymorphism is unlikely to play a major role in the pathogenesis of panic disorder. [Abstract]

Maron E, Lang A, Tasa G, Liivlaid L, Tõru I, Must A, Vasar V, Shlik J
Associations between serotonin-related gene polymorphisms and panic disorder.
Int J Neuropsychopharmacol. 2005 Jun;8(2):261-6.
Studies suggest that vulnerability to panic attacks and panic disorder (PD) may be related to a deficient serotonin (5-HT) neurotransmission. In the present case-control study we investigated possible associations between PD phenotype and five candidate polymorphisms including 5-HT transporter (5-HTTLPR and VNTR), monoamine oxidase A (MAOA promoter region), tryptophan hydroxylase 1 (TPH1 218A/C) and 5-HT1B receptor (5-HT1BR 861G/C) genes. The study sample consisted of 158 patients with PD and 215 healthy control subjects. The analysis showed higher frequencies of LL genotype (p = 0.016) and L allele variant (p = 0.007) of 5-HTTLPR in the patients. No significant associations were observed between PD and other candidate gene polymorphisms. However, a higher frequency of longer allele genotypes of the MAOA promoter region was observed in female PD patients with agoraphobia than in female controls (p = 0.016). These findings indicate that genetic variants conceivably related to lower 5-HT neurotransmission may be involved in the development of PD. [Abstract]

Perna G, Favaron E, Di Bella D, Bussi R, Bellodi L
Antipanic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene.
Neuropsychopharmacology. 2005 Dec;30(12):2230-5.
Serotonin selective reuptake inhibitors (SSRIs) are the drugs of choice in the treatment of panic disorder (PD). The serotonin transporter (5-HTT) is a prime target for SSRIs. A functional polymorphism within the promoter region of the 5-HTT gene, leading to different transcriptional efficiency, was repeatedly reported to influence the response to SSRIs in mood disorders while the response of patients with OCD seems unrelated. We tested the hypothesis that allelic variation of the 5-HTT promoter could be related to the antipanic response to paroxetine. In total, 92 patients with PD completed a treatment with a variable dose of paroxetine for 12 weeks. The severity of panic-phobic symptomatology was measured before the beginning of the treatment and after 12 weeks. Allelic variation in each subject was determined using a PCR-based method. Both homozygotes for the long variant (l/l) of the 5-HTT promoter and heterozygotes (l/s) showed a better response to paroxetine than homozygotes for the short variant (s/s) (chi(2)=6.9, p<0.03). This result emerged in the whole sample, but was related only to female patients (chi(2)=7.6, p<0.02). The presence of the long allelic variant was associated with a better response of panic attacks while was not significantly associated with the response of anticipatory anxiety or phobic avoidance. In conclusion, paroxetine efficacy in PD seems to be related to allelic variation within the promoter of the 5-HTT gene in female subjects. This gender effect might be related to the genomic effects of sex hormones. Understanding the interaction between gender and genes coding for structures target of psychotropic drugs could help to individualize the pharmacological treatment of PD. [Abstract]

Freitag CM, Domschke K, Rothe C, Lee YJ, Hohoff C, Gutknecht L, Sand P, Fimmers R, Lesch KP, Deckert J
Interaction of serotonergic and noradrenergic gene variants in panic disorder.
Psychiatr Genet. 2006 Apr;16(2):59-65.
OBJECTIVE: Panic disorder is an anxiety disorder with an estimated heritability of 48%. Associations findings have been obtained with candidate genes from both serotonergic and noradrenergic pathways including regulatory and coding variants of the serotonin receptor 1A gene, the monoamine oxidase A gene, the catechol-O-methyltransferase gene and the norepinephrine transporter gene. METHODS: In the present study, an analysis of interactions between the functional serotonin receptor 1A polymorphism, the norepinephrine transporter variants and the other respective polymorphisms of the above-mentioned genes is reported. The analysis is based on genotype results from 115 cases and 115 age and sex-matched controls. RESULTS: A nominally significant (P=0.04) interaction between the serotonin receptor 1A and the catechol-O-methyltransferase polymorphisms was observed. Stratified analysis revealed that the odds ratio of each polymorphism was highest in the presence of the low-risk genotype(s) of the other polymorphism and low in the presence of the high-risk genotype(s) of the other polymorphism. CONCLUSIONS: This is the first possible interaction of genetic variations in panic disorder that has been observed. As the sample size was small and no adjustment for multiple testing was made, the assessment of the interacting risk alleles needs replication in a larger sample with higher power. [Abstract]

Rothe C, Gutknecht L, Freitag C, Tauber R, Mössner R, Franke P, Fritze J, Wagner G, Peikert G, Wenda B, Sand P, Jacob C, Rietschel M, Nöthen MM, Garritsen H, Fimmers R, Deckert J, Lesch KP
Association of a functional 1019C>G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia.
Int J Neuropsychopharmacol. 2004 Jun;7(2):189-92.
Panic disorder is a common anxiety disorder which frequently co-occurs with agoraphobia. A functional promoter polymorphism in the serotonin receptor 1A (5-HT1A) gene has been found to be associated with major depression as well as anxiety- and depression-related personality traits. We investigated a possible association between this 5-HT1A gene promoter polymorphism and panic disorder by genotyping the 1019C>G single nucleotide polymorphism in 134 panic-disorder patients with and without agoraphobia and matched 134 controls. In our sample no significant evidence of allelic association in the combined panic-disorder group was found. However, our results show a significant association with the G allele in patients with panic disorder with agoraphobia (p=0.03, n=101). In conclusion, our findings do not support a major contribution of this polymorphism to the pathogenesis of panic disorder, but provide evidence for a possible role in the subgroup with agoraphobia. [Abstract]

Domschke K, Braun M, Ohrmann P, Suslow T, Kugel H, Bauer J, Hohoff C, Kersting A, Engelien A, Arolt V, Heindel W, Deckert J
Association of the functional -1019C/G 5-HT 1A polymorphism with prefrontal cortex and amygdala activation measured with 3 T fMRI in panic disorder.
Int J Neuropsychopharmacol. 2006 Jun;9(3):349-55.
Serotonergic genes have been implicated in the pathogenesis of panic disorder and amygdala function in response to fearful stimuli. Regional brain activation on visual presentation of emotional facial stimuli was investigated in 20 patients with panic disorder by means of fMRI at 3 T. All patients were genotyped for the functional -1019C/G 5-HT1A and 5-HTTLPR polymorphisms. In patients homozygous for the 5-HT1A -1019G risk allele (n=5), fearful stimuli were associated with a decreased activation of right prefrontal cortex regions. Patients homozygous for the 5-HT1A -1019G risk allele or patients carrying the short risk allele of the 5-HTTLPR (n=13) showed higher amygdala activation in response to happy faces. This exploratory study suggests a role of the functional -1019C/G 5-HT1A and 5-HTTLPR polymorphisms on prefrontal cortex and amygdala activation patterns in response to emotional facial stimuli. These serotonergic polymorphisms might increase the risk for panic disorder by contributing to an altered processing of emotional stimuli. [Abstract]

Ohara K, Xie DW, Ishigaki T, Deng ZL, Nakamura Y, Suzuki Y, Miyasato K, Ohara K.
The genes encoding the 5HT1D alpha and 5HT1D beta receptors are unchanged in patients with panic disorder.
Biol Psychiatry 1996 Jan 1;39(1):5-10
"To determine the serotonergic function in panic disorder, sequencing of the genes encoding the 5HT1D alpha and 5HT1D beta receptors was carried out. The genes for the 5HT1D alpha and 5HT1D beta receptors were amplified by polymerase chain reaction and sequenced by the dideoxy method. Some patients have both nucleotides C and T at position 1080 in 5HT1D alpha receptor gene; however, both of them code the same amino acid, asparagine. The 5HT1D beta receptor gene had a substitution from GCA276 to GCG276, not only panic disorder but also in controls; however, this substitution does not change the corresponding amino acid, alanine92." [Abstract]

Deckert J, Meyer J, Catalano M, Bosi M, Sand P, DiBella D, Ortega G, Stober G, Franke P, Nothen MM, Fritze J, Maier W, Beckmann H, Propping P, Bellodi L, Lesch KP.
Novel 5'-regulatory region polymorphisms of the 5-HT2C receptor gene: association study with panic disorder.
Int J Neuropsychopharmacol 2000 Dec;3(4):321-325
"Candidate genes for association studies in panic disorder are often selected on the basis of molecular mechanisms of drugs utilized in challenge tests such as m-chlorophenylpiperazine (mCPP), a non-selective 5-HT2C receptor agonist. Two novel, adjacent polymorphisms [(GT)12-18 and (CT)4-5] in the 5'-regulatory region of the X-chromosomal 5-HT2C receptor gene have recently been reported. We determined the allele frequency of long vs. short polymorphism haplotypes in a German and an Italian sample (combined n = 211) of panic disorder patients (DSM-III-R) and compared it with allele frequencies in two ethnically matched control samples (combined n = 226). In the German sample, a comparison of female genotypes containing the short haplotype vs. female genotypes containing only long haplotypes showed a significant difference (p = 0.01, ?2 analysis). In the Italian sample, however, this observation could not be replicated (p = 0.54, ?2 analysis). This argues against a major role for these promoter-associated 5-HT2C receptor gene length polymorphisms in the aetiopathogenesis of panic disorder." [Abstract]

Fehr C, Szegedi A, Anghelescu I, Klawe C, Hiemke C, Dahmen N.
Sex differences in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients and healthy volunteers: findings from an association study.
Psychiatr Genet 2000 Jun;10(2):59-65
"Polymorphisms in the serotonergic system are believed to play a role in the etiology and treatment of different psychiatric illnesses. The 5-HT2C receptor gene is X-linked, with a frequent mutation at nucleotide 68 leading to a Ser-->Cys transition at amino acid 23. Recent studies have demonstrated an impaired function of 5-HT2C receptors and an increased production of the major noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol in the cerebrospinal fluid among the subjects carrying the Ser23 allele (Lappalainen et al., 1999). Biol. Psychiatry 46:821). We genotyped patients with alcohol dependence, panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy and normal healthy volunteers for the 5-HT2C Cys23Ser polymorphism. 5-HT2C Cys23Ser allele frequencies and genotypes did not differ among patients with alcohol dependence, panic disorder, generalized anxiety disorder, narcolepsy and normal healthy volunteers. In an overall analysis, female subjects (n = 173) displayed a higher frequency of 5-HT2C Ser23 alleles as compared to males (n = 298, P = 0.0178). The potential mechanisms of the observed gender difference in allele frequencies, including transmission ratio distortion, are discussed." [Abstract]

Crawford F, Hoyne J, Diaz P, Osborne A, Dorotheo J, Sheehan D, Mullan M.
Occurrence of the Cys311 DRD2 variant in a pedigree multiply affected with panic disorder.
Am J Med Genet 1995 Aug 14;60(4):332-4
"Following the detection of the rare DRD2 codon 311 variant (Ser-->Cys) in an affected member from a large, multiply affected panic disorder family, we investigated the occurrence of this variant in other family members. The variant occurred in both affected and unaffected individuals. Further screening in panic disorder sib pairs unrelated to this family failed to detect the Cys311 variant. Our data suggests that this variant has no pathogenic role in panic disorder." [Abstract]

Stochino ME, Asuni C, Congiu D, Del Zompo M, Severino G
Association study between the phenotype migraine without aura-panic disorder and dopaminergic receptor genes.
Pharmacol Res. 2003 Nov;48(5):531-4.
Clinical and epidemiological evidence suggests that migraine often co-occurs with psychopathological conditions. Several longitudinal and population-based studies have suggested that migraine and panic disorder might share a common predisposition. An abnormal dopaminergic function has been hypothesized to be involved as etiological factor in panic disorder as well as in migraine. Epidemiological and molecular data suggest the role of genetic factors in the pathogenesis of both migraine and panic attack disorder. We assessed the presence of panic disorder in 100 probands suffering from migraine without aura and the present study was designed to analyse the possible association of the migraine-panic phenotype with dopaminergic genes. In our sample, 17 out of 100 migraineurs were affected by panic disorder and were thus considered for the genetic association study. The allele frequencies of DRD1, DRD3, DRD5, DRD2 in probands did not differ from that of parental non-transmitted chromosomes.This result does not seem to support, in our limited sample, a common pathological basis, with regard to the dopaminergic system, between migraine and panic. Should migraine and panic disorder share some common mechanisms, these could be sought in neuro-chemical systems other than the dopaminergic one. [Abstract]

Weissman MM, Gross R, Fyer A, Heiman GA, Gameroff MJ, Hodge SE, Kaufman D, Kaplan SA, Wickramaratne PJ
Interstitial cystitis and panic disorder: a potential genetic syndrome.
Arch Gen Psychiatry. 2004 Mar;61(3):273-9.
BACKGROUND: Evidence from a genetic linkage study had suggested a possible syndrome in some families with panic disorder (PD). This syndrome includes bladder problems (possibly urinary interstitial cystitis [IC]), thyroid disorders, chronic headaches/migraine, and/or mitral valve prolapse. In 19 multiplex families with PD, one marker (D13S779) on chromosome 13 gave a logarithm of odds score of more than 4 when individuals with any of the syndrome conditions were analyzed as affected. Families with the bladder problems yielded the highest logarithm of odds scores. These findings were replicated in an extended sample of 60 families. Whereas PD had been well characterized by direct interview, the urologic problems had been found only via medical history checklists and records. A case review by a board-certified urologist suggested they could be IC. OBJECTIVE: To determine whether patients diagnosed as having IC by urodynamics and/or cystoscopy and their first-degree relatives (FDRs) have increased rates of the syndrome conditions, thus validating that the bladder problems observed in the linkage study could be IC and providing further support for the panic syndrome. DESIGN: Case-control and family history study. SETTING: Two metropolitan urology clinics. PARTICIPANTS: One hundred forty-six probands (67 with IC and 79 with other urologic disorders) and 815 FDRs. MAIN OUTCOME MEASURES: Lifetime rates of syndrome conditions in probands and FDRs who were blind to urologic or psychiatric diagnoses in the proband. RESULTS: Compared with patients without IC, patients with IC had a significantly higher lifetime prevalence of PD (controlling for age and sex) (odds ratio, 4.05; 95% confidence interval, 1.22-13.40; P =.02) and a higher lifetime prevalence of any of the syndrome disorders (controlling for age and sex) (odds ratio, 2.22; 95% confidence interval, 0.89-5.54; P =.09). First-degree relatives of probands with (vs without) IC were significantly more likely to have PD, thyroid disorder, urologic problems, and any of the syndrome disorders (controlling for age and sex of the relative and sex of the proband) (adjusted odds ratio, 1.95; 95% confidence interval, 1.13-3.38; P =.02). These results in relatives were not influenced by PD in probands, and did not change substantially when controlling for the proband-relative relationship, modeling age as a categorical (vs continuous) variable, or excluding FDRs with PD. There were no interactions between proband IC status and sex of the relative. CONCLUSIONS: The increased frequency of seemingly disparate disorders in patients with IC and their FDRs is consistent with the genetic linkage findings in families with PD. These findings suggest that the bladder problems observed in the linkage study may be IC. The hypothesis that there is a familial, possibly pleiotropic, syndrome that may include IC, PD, thyroid disorders, and other disorders of possible autonomic or neuromuscular control deserves further investigation. [Abstract]

Crowe RR, Noyes R Jr, Samuelson S, Wesner R, Wilson R.
Close linkage between panic disorder and alpha-haptoglobin excluded in 10 families.
Arch Gen Psychiatry 1990 Apr;47(4):377-80
"We previously reported a lod score of 2.3 suggesting linkage between panic disorder and the alpha-haptoglobin locus on chromosome 16q22 in 26 pedigrees. In the present study we tested for linkage between alpha-haptoglobin and panic disorder in 10 new pedigrees and excluded a gene for panic disorder from 6 centimorgans (recombination fraction, 0.06) surrounding the alpha-haptoglobin locus. The data were analyzed under a variety of assumptions about the transmission of panic disorder, and linkage was excluded by all genetic models but one. When lod scores from the present set of 10 pedigrees were pooled with those from the first 26, no evidence of genetic heterogeneity was found, and the maximum lod score was 0.67 at a recombination fraction of 0.17. Taken as a whole, the present findings do not support the presence of a disease gene for panic disorder closely linked to the alpha-haptoglobin locus on chromosome 16q22." [Abstract]

Philibert RA, Nelson JJ, Bedell B, Goedken R, Sandhu HK, Noyes R Jr, Crowe RR.
Role of elastin polymorphisms in panic disorder.
Am J Med Genet 2003 Feb 15;117B(1):7-10
"Panic disorder (PD) is a complex neuropsychiatric disorder that has been associated with an increased frequency of mitral valve prolapse. Elastin is a prominent component of mitral valves and, in a genome screen of 23 pedigrees with PD, we found evidence of linkage to the region of chromosome 7 that contains the elastin gene (ELN). Therefore, we examined the minimal essential promoter and coding regions of ELN in 23 independent probands from the families in our linkage studies using single strand conformational polymorphism analysis. We found three polymorphisms including one that coded for a non-conservative amino acid change. However, none of these polymorphisms were associated with panic disorder in a case-control analysis or linked to it in multiplex pedigrees. In our pedigrees, exonic polymorphisms in ELN do not play a major role in the genetic vulnerability to PD." [Abstract]

Tharmalingam S, King N, De Luca V, Rothe C, Koszycki D, Bradwejn J, Macciardi F, Kennedy JL
Lack of association between the corticotrophin-releasing hormone receptor 2 gene and panic disorder.
Psychiatr Genet. 2006 Jun;16(3):93-97.
Panic disorder is classified as an anxiety disorder and affects 1-3% of the population. An individual suffering from such a disorder may experience unexpected recurrent panic attacks and fear of future attacks. Twin and family studies have pointed towards a strong heritability of the disorder. Stress response and anxiety are thought to be mediated, at least in part, by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway. To search for markers conferring genetic susceptibility to panic disorder, we typed three polymorphisms of the CRHR2 gene - CRHR2(CA), CRHR2(GT), and CRHR2(GAT) - in 466 individuals, 183 of whom had DSM-IV panic disorder. Seventy-five case-controls and 101 triad families plus 13 siblings were examined. Case-control association analyses using chi tests yielded no difference in the distribution of the alleles. Linkage analysis using the Transmission Disequilibrium Test showed no preferential transmission of alleles for any of the three markers. Haplotype analysis indicated that allele 7 of CRHR2 (GAT) and 8 of CRHR2 (GT) are in almost complete linkage disequilibrium (P=0.000 000 1). Although both neurobiology and chromosomal location point to the CHRH2 receptor gene as a candidate for panic disorder, our study indicates that the CRHR2 polymorphisms examined do not confer susceptibility to panic disorder. Further studies investigating additional polymorphisms in this gene and other components of the CRH signalling system may prove useful. [Abstract]