Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study
Abstract
AIMS: The gamma-aminobutyric acid receptor A (GABRA) gene clusters on chromosomes 4 and 5 have been examined previously for their association with alcohol and drug dependence phenotypes. Compelling evidence suggests that GABRA2 is associated with alcohol and drug dependence. However, no study has investigated whether genes in the GABA(A) gene clusters are associated with nicotine dependence, an important phenotype with a high correlation to persistent smoking, the single most preventable cause of mortality world-wide. DESIGN: Using data on 1050 nicotine-dependent cases and 879 non-dependent smoking controls, we used logistic regression to examine the association between single nucleotide polymorphisms (SNPs) in 13 genes in the GABA(A) receptor system as well as GABBR2 (a GABA(B) gene). FINDINGS: We found evidence for association between four SNPs in GABRA4, two SNPs in GABRA2 and one SNP in GABRE with nicotine dependence. These included a synonymous polymorphism in GABRA2 (rs279858), lying in a highly conserved region, which has been shown previously to be associated with alcohol and drug dependence. A non-synonymous polymorphism (rs16859834/rs2229940) in GABRA4, also highly conserved, was associated at P-value of 0.03. Significant haplotypes associated with nicotine dependence were found for GABRA2. No evidence for epistatic interactions were noted. Our study did not find evidence for an association between GABBR2 gene and nicotine dependence. CONCLUSIONS: Given the potential role of compounds that enhance GABAergic neurotransmission in smoking cessation research, these findings have enormous potential for informing the wider field of addiction research.
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GABAARs in brain reward circuits may be involved in the development of brain changes that mediate the addictive properties of drugs in general.
“The involvement of GABAAR genes in the abuse of and dependence on drugs that do not directly affect the GABAARs suggest that the GABAARs in brain reward circuits may be involved in the development of brain changes that mediate the addictive properties of drugs in general.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [102]
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An emerging circuit pharmacology of GABAA receptors
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Self-citationLind, P. A., Macgregor, S., Agrawal, A., Montgomery, G. W., Heath, A. C., Martin, N. G., & Whitfield, J. B. (2008) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00768.x · Cited by 55 · see citing works
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- Authors
- Agrawal, A., Pergadia, M. L., Saccone, S. F., Hinrichs, A. L., Lessov‐Schlaggar, C. N., Saccone, N. L., Neuman, R. J., Breslau, N., Johnson, E., Hatsukami, D., Montgomery, G. W., Heath, A. C., Martin, N. G., Goate, A. M., Rice, J. P., Bierut, L. J., & Madden, P. A. F.
- Affiliations
- Washington University in St. Louis (US)
- SRI International (US)
- Michigan State University (US)
- RTI International (US)
- University of Minnesota (US)
- QIMR Berghofer Medical Research Institute (AU)
- ORCID
- Venue
- Addiction
- Publisher
- Wiley
- Published
- 2008-06
- Volume
- 103
- Issue
- 6
- Pages
- 1027-1038
- ISSN
- 0965-2140 (ISSN-L)
- 1360-0443
- OpenAlex
- W2133217404
- Cited by
- 56
- References
- 68
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 7 · 2017: 1 · 2016: 7 · 2015: 3 · 2014: 3 · 2013: 1 · 2012: 3
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Addiction (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (HHSN271200477471C)
- National Institute on Drug Abuse (DA 019951, DA12854, DA015129, N01DA07079, K01DA015129, K08DA019951)
- National Cancer Institute (CA89392, P01CA089392)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- nicotine dependence, GABRA2, GABRA4, GABBR2, single nucleotide polymorphisms, haplotypes, smoking, genetic association, GABAergic neurotransmission, addiction genetics
- MeSH terms
- Chromosomes, Human, 4-5, Female, Genotype, Humans, Male, Phenotype, Tobacco Use Disorder, Logistic Models, Case-Control Studies, Smoking Cessation, Behavior, Addictive, Receptors, GABA, Evidence-Based Medicine
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