Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence
Open accessAbstract
Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.
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CHRNA5 mRNA levels show high interindividual variability in both frontal cortex and lymphocytes.
“Expression studies have demonstrated that CHRNA5 mRNA levels show high interindividual variability in both frontal cortex and lymphocytes (99).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [99]
Rs588765 impacts the expression of CHRNA5 in human brain tissue, with subjects homozygous for two minor alleles (TT) showing the highest CHRNA5 mRNA expression.
“Rs588765 impacts the expression of CHRNA5 in human brain tissue 46 with subjects homozygous with two minor alleles (TT) showing the highest CHRNA5 mRNA expression. 46”
From Depressive symptoms predict clinical recurrence of inflammatory bowel disease (2022) · cites this paper as [46]
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- Authors
- Wang, J. C., Grucza, R., Cruchaga, C., Hinrichs, A. L., Bertelsen, S., Budde, J. P., Fox, L., Goldstein, E., Reyes, O., Saccone, N., Saccone, S., Xuei, X., Bucholz, K., Kuperman, S., Nurnberger, J., Rice, J. P., Schuckit, M., Tischfield, J., Hesselbrock, V, Porjesz, B., Edenberg, H. J., Bierut, L. J., & Goate, A. M.
- Affiliations
- Washington University in St. Louis (US)
- Indiana University Indianapolis (US)
- University of California San Diego (US)
- Rutgers, The State University of New Jersey (US)
- University of Connecticut (US)
- Corresponding author
- Goate, A M
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2008-04-15
- Volume
- 14
- Issue
- 5
- Pages
- 501-510
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4381434
- OpenAlex
- W2093357561
- Cited by
- 226
- References
- 55
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 9 · 2019: 4 · 2018: 11 · 2017: 8 · 2016: 13 · 2015: 21 · 2014: 20 · 2013: 26 · 2012: 20
- FWCI
- 14.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- SUNY Digital Repository Support (State University of New York System) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R28AA012725, U10AA008401)
- National Institute on Aging (P50AG005681, P01AG003991, P01AG026276)
- National Institute on Drug Abuse (R01DA019963, R01DA013423)
- National Cancer Institute (P01CA089392)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- alcoholism, CHRNA5, CHRNA3, CHRNB4, nicotinic acetylcholine receptor genes, genetic polymorphism, mRNA levels, family-based association, nicotine dependence, gene expression, linkage disequilibrium, alcoholism genetics
- MeSH terms
- Alcoholism, Brain, Family Health, Gene Frequency, Genotype, Humans, Nerve Tissue Proteins, Receptors, Nicotinic, Risk, RNA, Messenger, Linkage Disequilibrium, Cluster Analysis, Logistic Models, Cocaine-Related Disorders, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Diagnostic and Statistical Manual of Mental Disorders, Genome-Wide Association Study
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