Evidence for the gamma-amino-butyric acid type B receptor 1 (GABBR1) gene as a susceptibility factor in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a well-recognized severe neuropsychiatric illness. Genetic factors are believed to be important etiologically. Although historically genetic testing has focused on the serotonergic and dopaminergic systems, there is increasing evidence that the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), may also be functionally involved. Furthermore the GABA type B receptor 1 (GABBR1) gene has been localized to chromosome 6p21.3 region, which has shown linkage to OCD. We investigated five polymorphisms (A-7265G substitution; C10497G substitution; A33795G substitution in the 3'-UTR; Ser-491-Ser-T1473C transition; Phe-659-Phe-T1977C transition) in the GABBR1 gene in a sample of 159 DSM-IV OCD probands and their families, using the transmission disequilibrium test (TDT). A trend was observed with an over-transmission of -7265A allele at the A-7265G polymorphism and OCD (chi2 = 3.270, P = 0.071). Moreover, the TDT haplotype analysis using TRANSMIT showed a trend toward association with the haplotype of the five polymorphisms together [2.1.1.2.1 (A-7265G.C10497G.Ser-491-Ser.Phe-659-Phe.A33795G)] with a Chi-square value of 3.418, which corresponds to a P-value of 0.065 (overall chi2 = 6.353, 5 df, P = 0.273). Moreover, a trend was observed for the total Yale-Brown obsessive-compulsive scale score in the A-7265G polymorphism (-7265A: z = 1.934, P = 0.053) using the Family-Based Association Test, considering the diagnosis of OCD and then the clinically relevant quantitative phenotypes. The observed trends suggest that further investigations of the role of the GABBR1 gene in OCD are warranted. Copyright 2005 Wiley-Liss, Inc.