Neuropsychopharmacology (2014) 39, 907–918 & 2014 American College of Neuropsychopharmacology. All rights reserved 0893-133X/14
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Association of Gamma-Aminobutyric Acid A Receptor a2 Gene (GABRA2) with Alcohol Use Disorder
,1,2,3,4 2 5 6,7 8 1,7,9 Dawei Li* , Arvis Sulovari , Chao Cheng , Hongyu Zhao , Henry R Kranzler and Joel Gelernter
1 2 Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA; Department of Microbiology and Molecular Genetics, 3 4 University of Vermont, Burlington, VT, USA; Department of Computer Science, University of Vermont, Burlington, VT, USA; Neuroscience, 5 Behavior, and Health Initiative, University of Vermont, Burlington, VT, USA; Department of Genetics, Geisel School of Medicine, Dartmouth 6 7 College, Hanover, NH, USA; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA; Department of Genetics, School of 8 Medicine, Yale University, New Haven, CT, USA; Department of Psychiatry, Perelman School of Medicine of the University of Pennsylvania and
Philadelphia VAMC, Philadelphia, PA, USA; 9VA Connecticut Healthcare Center, West Haven, CT, USA
Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in mammalian brain. GABA receptor are involved in a number of
complex disorders, including substance abuse. No variants of the commonly studied GABA receptor genes that have been associated with
substance dependence have been determined to be functional or pathogenic. To reconcile the conflicting associations with substance
dependence traits, we performed a meta-analysis of variants in the GABAA receptor genes (GABRB2, GABRA6, GABRA1,andGABRG2 on
chromosome 5q and GABRA2 on chromosome 4p12) using genotype data from 4739 cases of alcohol, opioid, or methamphetamine
dependence and 4924 controls. Then, we combined the data from candidate gene association studies in the literature with two alcohol
dependence (AD) samples, including 1691 cases and 1712 controls from the Study of Addiction: Genetics and Environment (SAGE), and
2644 cases and 494 controls from our own study. Using a Bonferroni-corrected threshold of 0.007, we found strong associations between 6 5 GABRA2 and AD (P ¼ 9 10 and odds ratio (OR) 95% confidence interval (CI) ¼ 1.27 (1.15, 1.4) for rs567926, P ¼ 4 10 and
OR ¼ 1.21 (1.1, 1.32) for rs279858), and between GABRG2 and both dependence on alcohol and dependence on heroin (P ¼ 0.0005 and
OR ¼ 1.22 (1.09, 1.37) for rs211014). Significant association was also observed between GABRA6 rs3219151 and AD. The GABRA2
rs279858 association was observed in the SAGE data sets with a combined P of 9 10 6 (OR ¼ 1.17 (1.09, 1.26)). When all of these data
sets, including our samples, were meta-analyzed, associations of both GABRA2 single-nucleotide polymorphisms remained (for rs567926,