Association Analysis of Chromosome 5 GABAA Receptor Cluster in Japanese Schizophrenia Patients

Background Several investigations suggest that abnormalities in γ-amino butyric acid (GABA) neurotransmission systems may be related to the pathophysiology of schizophrenia. A GABAA receptor gene cluster on 5q31-35 (β2 [GABRB2], α6 [GABRA6], α1 [GABRA1], and γ2 [GABRG2] subunit genes) is one of the most attractive candidate regions for schizophrenia susceptibility. Methods We performed 1) systematic polymorphism search of GABRB2, GABRA6, and GABRA1, in addition to our colleague’s study of GABRG2; 2) evaluation of linkage disequilibrium (LD) within this cluster with 35 single nucleotide polymorphisms (SNPs); 3) “selection of haplotype-tagging (ht) SNPs”; and 4) two-stage association analysis that comprised first-set screening analysis of all htSNPs (288 Japanese schizophrenia patients and 288 control subjects) and second-set replication analysis of the positive htSNPs (901 schizophrenic patients and 806 control subjects). Results In the first-set scan, we found a significant association of two htSNPs in GABRA1, but no association of GABRB2, GABRA6, and GABRG2. In the following second-set analysis, however, we could not confirm these significant associations. Conclusions These results indicate that this gene cluster may not play a major role in Japanese schizophrenia. They also raised an alert with regard to preliminary genetic association analysis using a small sample size.