Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR)

Abstract

Panic disorder (PD) and social anxiety disorder (SAD) are moderately heritable anxiety disorders. We analyzed five genes, derived from pharmacological or translational mouse models, in a new case-control study of PD and SAD in European Americans: (1) the serotonin transporter (SLC6A4), (2) the serotonin receptor 1A, (3) catechol-O-methyltransferase, (4) a regulator of g-protein signaling and (5) the gastrin-releasing peptide receptor. Cases were interviewed using the schedule for affective disorders and schizophrenia and were required to have a probable or definite lifetime diagnosis of PD (N = 179), SAD (161) or both (140), with first onset by age 31 and a family history of anxiety. Final diagnoses were determined using the best estimate procedure, blind to genotyping data. Controls were obtained from the National Institute of Mental Health Human Genetics Initiative; only subjects above 25 years of age who screened negative for all psychiatric symptoms were included (N = 470). A total of 45 single nucleotide polymorphisms were successfully genotyped over the five selected genes using Applied Biosystems SNPlex protocol. SLC6A4 provided strong and consistent evidence of association with the PD and PD þ SAD groups, with the most significant association in both groups being at rs140701 (v 2 = 10.72, P = 0.001 with PD and v 2 = 8.59, P = 0.003 in the PD þ SAD group). This association remained significant after multiple test correction. Those carrying at least one copy of the haplotype A-A-G constructed from rs3794808, rs140701 and rs4583306 have 1.7 times the odds of PD than those without the haplotype (95% confidence interval: 1.2-2.3). The SAD only group did not provide evidence of association, suggesting a PD-driven association. The findings remained after adjustment for age and sex, and there was no evidence that the association was due to population stratification. The promoter region of the gene, 5-HTTLPR, did not provide any evidence of association, regardless of whether analyzed as a triallelic or biallelic locus, nor did any of the other four candidate genes tested. Our findings suggest that the serotonin transporter gene may play a role in PD; however, the findings require replication. Future studies should attend to the entire genetic region rather than the promoter.

Genotypes over-represented among college students are linked to better cognitive abilities and socioemotional adjustment

“…In our college sample, the homozygotes were underrepresented while the heterozygotes were overrepresented. Second, the G allele of SNP rs4583306 of SLC6A4 (in an LD block) has been linked to panic disorder (Strug et al 2008) and mood disorder in subjects who experienced childhood physical abuse (Brezo et al 2009), whereas the heterozygotes were overrepresented in our college sample. Third, it was reported that the G allele of SNP rs10488683 of TPH1 was linked to the diathesis for suicide attempts (Brezo et al 2009), whereas our study showed a slight overrepresentation of the A allele homozygotes among college students.…”

“…Among the five alleles that have been linked to mental health issues/disorders, the results are generally consistent with our hypothesis. First, the minor allele (G) of rs140701 of SLC6A4 was linked to major depression disorder (Dong et al 2009), and the major allele (A) was linked to panic disorder (Strug et al 2008). In our college sample, the homozygotes were underrepresented while the heterozygotes were overrepresented.…”

Advances in molecular genetics of panic disorder

“…This functional variant in the coding sequence of COMT gene has attracted a number of studies in various PD-related phenotypes (see Table 1). 22,[120][121][122][123][124][125][126][127] A recent meta-analysis of six available case-control studies showed significant association of the COMT 158 Val allele with PD in the Caucasian samples and, conversely, a trend toward association of the COMT 158 Met allele with PD in the Asian samples. 128 Interestingly, stratification for gender as well as ethnicity revealed that the associations of the 158 Val allele in Caucasians and, reciprocally, the 158 Met allele in Asians were restricted to females.…”

“…99 An Italian study reported that the high-expressive L variant of 5-HTTLPR was associated with a better response to 12-week treatment with an SSRI paroxetine in female patients with PD, 100 but this finding was not replicated in a Korean PD sample. 101 Recently, Strug et al 22 showed strong and consistent association across several SNPs in the SLC6A4 gene and PD phenotype, the most significant association being at rs140701. However, these results may have been confounded by a significant gender disproportion between studied groups, in which more females were included in PD sample compared to controls (see Table 1).…”

“…44 However, several other studies did not confirm the association between this polymorphism and PD. 22,45 Neurobiological analyses provide mixed support for the role of this polymorphism in PD pathophysiology. In one study, a significantly lower activation in several brain regions, including the right ventromedial, orbitofrontal, and anterior cingulate cortices, was found in PD patients homozygous for the G high-risk allele of the HTR1A rs6295C/G polymorphism during processing of anxiety-related facial expressions.…”