title: Genetic variation in GABRβ1 and the risk for developing alcohol dependence.
abstract: Associations between the γ-aminobutyric acid type-A receptors (GABAA) and alcohol dependence risk have been reported, although the receptor subunit driving the association is unclear. Recent work in mice has highlighted a possible role for variants in the Gabr β1 subunit (Gabrβ1) in alcohol dependence risk, although this gene does not contain any common nonsynonymous variants in humans. However, the GABAA receptor is a heteropentamer so multiple potential variants within the gene complex could generate the alcohol dependence phenotype. The association between GABRβ1 variants and alcohol dependence risk was explored in a British and Irish population of alcohol-dependent cases (n=450) and ancestrally-matched controls screened to exclude current or historical alcohol misuse (n=555). Twelve common single nucleotide polymorphisms (SNPs) and a rare nonsynonymous variant, rs41311286, were directly genotyped; imputation was then performed across the whole gene. No allelic association was observed between alcohol dependence risk and any of the directly genotyped or imputed SNPs. However, post-hoc testing for genotypic association identified five common intronic SNPs that showed modest evidence for association after correction for multiple testing; two, rs76112682 and rs141719901, were in complete linkage disequilibrium [Pcorrected=0.02, odds ratio (95% confidence interval)=5.9 (1.7-2.06)]. These findings provide limited support for an association between GABRβ1 and the risk for developing alcohol dependence; further testing in expanded cohorts may be warranted.
authors.affiliation: aUCL Institute for Liver & Digestive Health, Division of Medicine bMolecular Psychiatry Laboratory, Division of Psychiatry, University College London cDepartment of Gastroenterology and Hepatology, Imperial College, St Mary's Hospital Campus, London dInstitute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: William A
authors.initials: WA
authors.lastname: McCabe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Way
authors.forename: Kush
authors.initials: K
authors.lastname: Ruparelia
authors.forename: Susanne
authors.initials: S
authors.lastname: Knapp
authors.forename: M Adam
authors.initials: MA
authors.lastname: Ali
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.forename: Howard C
authors.initials: HC
authors.lastname: Thomas
authors.forename: Andrew
authors.initials: A
authors.lastname: McQuillin
authors.forename: Marsha Y
authors.initials: MY
authors.lastname: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism / Q000235:genetics*; D000483:Alleles; D005260:Female; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D051268:GA-Binding Protein Transcription Factor; C495662:GABPB1 protein, human