Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders.

BACKGROUND: GABRB3 is a position candidate gene at chromosome 15q12 that has been implicated in the neurobiology of autism spectrum disorders (ASD). The aim of this study was to examine the genetic association of GABRB3 with ASD. METHODS: The sample consisted of 356 patients with clinical diagnosis of ASD according to the DSM-IV diagnostic criteria and confirmed by the Autism Diagnostic Interview-Revised and 386 unrelated controls. We searched for mutations at all the exonic regions and 1.6 Kb of the 5' region of GABRB3 in the genomic DNA of all the participants using the Sanger sequencing. We implemented a case-control association analysis of variants detected in this sample, and conducted a reporter gene assay to assess the functional impact of variants at the 5' regulatory region. RESULTS: We detected six known common SNPs; however, they were not associated with ASD. Besides, a total of 22 rare variants (12 at 5' regulatory, 4 at intronic, and 6 at exonic regions) were detected in 18 patients and 6 controls. The frequency of rare variants was significantly higher in the patient group than in the control group (18/356 versus 6/386, odds ratio = 3.37, P = 0.007). All the 12 rare variants at the 5' regulatory region were only detected in 7 patients, but not in any of the controls (7/356 versus 0/386, Fisher's exact test, P = 0.006). Two patients carried multiple rare variants. Family studies showed that most of these rare variants were transmitted from their parents. Reporter gene assays revealed that four rare variants at the 5' regulatory region and 1 at exon 1a untranslated region had elevated reporter gene activities compared to two wild type alleles. CONCLUSIONS: Our data suggest rare variants of GABRB3 might be associated with ASD, and increased GABRB3 expression may contribute to the pathogenesis of ASD in some patients. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION IDENTIFIER: NCT00494754.