Polymorphisms in the GAD2 gene-region are associated with susceptibility for unipolar depression and with a risk factor for anxiety disorders

Glutamate decarboxylase (GAD) is the rate limiting enzyme for conversion of glutamic acid to gamma-aminobutyric acid (GABA). The GAD 65 kDa isoform is encoded by the gene GAD2 and is mainly expressed in synaptic terminals. It serves as an apoenzyme, which shows enhanced availability in situations of stress, responding to short-term demands for GABA. We analyzed 18 single nucleotide polymorphisms (SNPs) in the GAD2-gene region for associations with psychiatric diagnosis and behavioral inhibition (BI) derived from the personality traits neuroticism and extraversion as defined by the Eysenck Personality Questionaire (EPQ). A total of 268 patients with anxiety disorder (AD), 541 with unipolar depression (MD), and 541 healthy controls were included. We observe associations for five tag-SNPs with BI in the AD- and control samples as well as two additional case-control associations in the MD-sample. The associated SNPs lie within a 16KB linkage disequilibrium-block, including putative 5' GAD2-promoter-elements as well as the 3' end of the gene MYO3A. Using open access mRNA-expression data, we could show that BI-associated SNPs appear to be associated with differences in MYO3A- but not GAD2 lymphoblastoid-mRNA expression levels. These results support earlier studies that suggest associations of polymorphisms within the GAD2 locus with anxiety and affective disorders. However, data from expression studies imply that these polymorphisms could tag functional effects on the neighboring gene MYO3A, which is also expressed in the brain, including the cingulate cortex and the amygdala.