Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder
Open accessAbstract
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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Human genetics studies have noted associations between GABAAR genes and different aspects of alcoholism.
“Human genetics studies have noted associations between GABAAR genes and different aspects of alcoholism [93-98].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [98]
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An emerging circuit pharmacology of GABAA receptors
Engin, E., Benham, R. S., & Rudolph, U. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.04.003 · Cited by 225 · see citing works
- Authors
- Li, D., Sulovari, A., Cheng, C., Zhao, H., Kranzler, H. R., & Gelernter, J.
- Affiliations
- University of Vermont (US)
- Dartmouth College (US)
- Yale University (US)
- Philadelphia VA Medical Center (US)
- Corresponding author
- Li, Dawei
- Venue
- Neuropsychopharmacology
- Published
- 2013-10-18
- Volume
- 39
- Issue
- 4
- Pages
- 907-918
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3924525
- OpenAlex
- W2063434016
- Cited by
- 103
- References
- 71
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 7 · 2018: 11 · 2017: 17 · 2016: 13 · 2015: 16 · 2014: 6
- FWCI
- 7.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA 12870, AA017535, R01AA017535, R01AA011330, P50AA012870, U10AA008401)
- National Institute on Drug Abuse (DA-12849, DA 12690, DA030976, R01DA030976, R01DA019963, R01DA012690, R01DA013423, R01DA018432, RC2DA028909, DA18432, R01DA012849)
- National Human Genome Research Institute (U01HG004422, HHSN268200782096C)
- National Cancer Institute (P01CA089392)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- GABRA2, GABAA receptor, alcoholism, heroin addiction, opioid use disorder, methamphetamine dependence, single nucleotide polymorphisms, GABRG2, GABRA6, GABRB2, genetic association
- MeSH terms
- Alcoholism, Female, Genotype, Humans, Male, Receptors, GABA-A, Reference Values, Retrospective Studies, Linkage Disequilibrium, Odds Ratio, Computational Biology, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Black People, White People
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