Abstract
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, and GABRG2 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 GABRA2 and AD (P=9 × 10−6 and odds ratio (OR) 95% confidence interval (CI)=1.27 (1.15, 1.4) for rs567926, P=4 × 10−5 and OR=1.21 (1.1, 1.32) for rs279858), and between GABRG2 and both dependence on alcohol and dependence on heroin (P=0.0005 and OR=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=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, P=7 × 10−5 (OR=1.18 (1.09, 1.29)) in all the studies, and P=8 × 10−6 (OR=1.25 (1.13, 1.38)) in subjects of European ancestry and for rs279858, P=5 × 10−6 (OR=1.18 (1.1, 1.26)) in subjects of European ancestry. Findings from this extensive meta-analysis of five GABAA receptor genes and substance abuse support their involvement (with the best evidence for GABRA2) in the pathogenesis of AD. Further replications with larger samples are warranted.
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Acknowledgements
This work was supported by the research grants DA12690, DA12849, DA18432, RC2DA028909, DA030976, AA11330, AA12870, and AA017535 from the National Institutes of Health, and by the Start-up Fund from University of Vermont, USA. Some genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268200782096C. The Study of Addiction: Genetics and Environment (SAGE) described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) through accession number phs000092.v1.p1. Funding support for SAGE was provided through U01 HG004422, U10 AA008401, P01 CA089392, R01 DA013423, and R01 DA019963. We also thank the reviewers and editor for providing helpful comments.
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Accession numbers and URLs for the data of the GABRB2, GABRA6, GABRA1, GABRG2, and GABRA2 genes in this article are as follows:
GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ for genomic structure;
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim;
Genotype data, http://www.hapmap.org/;
Genome data, http://genome.ucsc.edu/.
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Li, D., Sulovari, A., Cheng, C. et al. Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder. Neuropsychopharmacol 39, 907–918 (2014). https://doi.org/10.1038/npp.2013.291
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