Abstract
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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Acknowledgements
The Collaborative Study on the Genetics of Alcoholism (COGA)—co-principal investigators B Porjesz, V Hesselbrock, H Edenberg, L Bierut—includes nine different centers where data collection, analysis and storage take place. The nine sites and principal investigators and co-investigators are University of Connecticut (V Hesselbrock), Indiana University (HJ Edenberg, J Nurnberger Jr, PM Conneally, T Foroud), University of Iowa (S Kuperman, R Crowe), SUNY Downstate (B Porjesz), Washington University in St Louis (L Bierut, A Goate, J Rice), University of California at San Diego (M Schuckit), Howard University (R Taylor), Rutgers University (J Tischfield), Southwest Foundation (L Almasy). Zhaoxia Ren serves as the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA008401 from the NIAAA and the National Institute on Drug Abuse (NIDA).
In memory of Henri Begleiter and Theodore Reich, Principal and co-principal investigators of COGA since its inception; we are indebted to their leadership in the establishment and nurturing of COGA, and acknowledge with great admiration their seminal scientific contributions to the field.
We are grateful to the families for their participation in the studies at St Louis Alzheimer's Disease Research Center (ADRC), Washington University. Funding for the research at ADRC was provided by grants from the National Institute on Aging: P50 AG05681 and P01 AG03991 to John C Morris. The Family Study of Cocaine Dependence (FSCD) data collection was funded by the National Institute of Drug Abuse (NIDA), R01 DA13423 to Laura J Bierut. Genotyping and analysis of the FSCD data was supported through the Case Control Candidate Gene Study of Addiction, NIDA grant R01 DA19963 to Laura J Bierut.
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Drs LJ Bierut, AM Goate, AJ Hinrichs, JP Rice, SF Saccone and JC Wang are listed as inventors on a patent (US 20070258898) held by Perlegen Sciences Inc., covering the use of certain SNPs, including rs16969968 in diagnosing, prognosing and treating addiction. Dr Bierut has acted as a consultant for Pfizer Inc. in 2008.
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Wang, J., Grucza, R., Cruchaga, C. et al. Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol Psychiatry 14, 501–510 (2009). https://doi.org/10.1038/mp.2008.42
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DOI: https://doi.org/10.1038/mp.2008.42
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