Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence

J. C. Wang, R. Grucza, C. Cruchaga, A. L. Hinrichs, S. Bertelsen, J. P. Budde, L. Fox, E. Goldstein, O. Reyes, N. Saccone, S. Saccone, X. Xuei, K. Bucholz, S. Kuperman, J. Nurnberger, J. P. Rice, M. Schuckit, J. Tischfield, V. Hesselbrock, B. PorjeszH. J. Edenberg, L. J. Bierut, A. M. Goate

Research output: Contribution to journalArticle

156 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)501-510
Number of pages10
JournalMolecular Psychiatry
Volume14
Issue number5
DOIs
StatePublished - May 1 2009

Fingerprint

Alcoholism
Messenger RNA
Genes
Tobacco Use Disorder
Smoking
Diagnostic and Statistical Manual of Mental Disorders
Addictive Behavior
Cocaine-Related Disorders
Linkage Disequilibrium
3' Untranslated Regions
Missense Mutation
Multigene Family
Nicotine
Single Nucleotide Polymorphism
Exons
Logistic Models
Observation
Brain

Keywords

  • Alcohol dependence
  • mRNA expression
  • Nicotinic acetylcholine receptors
  • Polymorphism

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Wang, J. C., Grucza, R., Cruchaga, C., Hinrichs, A. L., Bertelsen, S., Budde, J. P., ... Goate, A. M. (2009). Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Molecular Psychiatry, 14(5), 501-510. https://doi.org/10.1038/mp.2008.42

Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. / 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.

In: Molecular Psychiatry, Vol. 14, No. 5, 01.05.2009, p. 501-510.

Research output: Contribution to journalArticle

Wang, JC, Grucza, R, Cruchaga, C, Hinrichs, AL, Bertelsen, S, Budde, JP, Fox, L, Goldstein, E, Reyes, O, Saccone, N, Saccone, S, Xuei, X, Bucholz, K, Kuperman, S, Nurnberger, J, Rice, JP, Schuckit, M, Tischfield, J, Hesselbrock, V, Porjesz, B, Edenberg, HJ, Bierut, LJ & Goate, AM 2009, 'Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence', Molecular Psychiatry, vol. 14, no. 5, pp. 501-510. https://doi.org/10.1038/mp.2008.42
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. / Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. In: Molecular Psychiatry. 2009 ; Vol. 14, No. 5. pp. 501-510.
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