1. ¹Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
2. ²Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA
3. ³Department of Biochemistry and Molecular Genetics, Indiana University, Indianapolis, IN, USA
4. ⁴Division of Child Psychiatry, University of Iowa, Iowa City, IA, USA
5. ⁵Department of Psychiatry, Indiana University, Indianapolis, IN, USA
6. ⁶Department of Psychiatry, San Diego VA Medical Center, UCSD, San Diego, CA, USA
7. ⁷Department of Genetics/HGI, Rutgers University, Piscataway, NJ, USA
8. ⁸Department of Psychiatry, University of Connecticut, Farmington, CT, USA
9. ⁹Department of Psychiatry, SUNY Health Science Center, Brooklyn, NY, USA
10. ¹⁰Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA

Correspondence: Professor A Goate, Department of Psychiatry, School of Medicine, Washington University, 660 S. Euclid, Saint Louis, MO 63110, USA. E-mail: goate@icarus.wustl.edu

Received 21 October 2007; Revised 10 March 2008; Accepted 10 March 2008; Published online 15 April 2008.

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.