The GABA transporter 1 (SLC6A1): a novel candidate gene for anxiety disorders

Abstract

Recent evidence suggests that the GABA transporter 1 (GAT-1; SLC6A1) plays a role in the pathophysiology and treatment of anxiety disorders. In order to understand the impact of genetic variation within SLC6A1 on pathological anxiety, we performed a case-control association study with anxiety disorder patients with and without syndromal panic attacks. Using the method of sequential addition of cases, we found that polymorphisms in the 5' flanking region of SLC6A1 are highly associated with anxiety disorders when considering the severity of syndromal panic attacks as phenotype covariate. Analysing the effect size of the association, we observed a constant increase in the odds ratio for disease susceptibility with an increase in panic severity (OR approximately 2.5 in severely affected patients). Nominally significant association effects were observed considering the entire patient sample. These data indicate a high load of genetic variance within SLC6A1 on pathological anxiety and highlight GAT-1 as a promising target for treatment of anxiety disorders with panic symptoms.

Fig. 1

Illustration and mapping of case–control P values (nominal) for genotyped SNPs at the SLC6A1 locus (upper graph). Lower triangular graph illustrates linkage disequilibrium (LD) and block structure within the GAT-1 gene using D′ as a measure for LD

Fig. 2

Sequential analysis of patient subsets versus controls. Illustration of nominal P values for all genotyped SNPs in the genomic order as presented for the analysis of patient subset V versus controls (a). Constant increases of the odds ratio (OR) along clusters for rs2930152 and rs2697153; dotted lines assign upper and lower confidence intervals of 95% (b). Distribution of alleles (%) of rs2930152 and rs2697153 within anxiety disorder patients of subset V (n = 60; black bars) and controls (n = 267; white bars); numbers indicate the total number of alleles in each group (c)