@article{dc8418bd4fae4a9883629390947fe205,
title = "A Risk Allele for Nicotine Dependence in CHRNA5 Is a Protective Allele for Cocaine Dependence",
abstract = "Background: A nonsynonymous coding polymorphism, rs16969968, of the CHRNA5 gene that encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence. The goal of this study was to examine the association of this variant with cocaine dependence. Methods: Genetic association analysis was performed in two independent samples of unrelated case and control subjects: 1) 504 European Americans participating in the Family Study on Cocaine Dependence (FSCD) and 2) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholism (COGA). Results: In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (odds ratio = .67 per allele, p = .0045, assuming an additive genetic model), but in the reverse direction compared with that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD. Conclusions: The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways.",
keywords = "Addiction, cocaine, genetics, nicotine dependence, nicotinic receptors, smoking, substance use disorders",
author = "Grucza, {Richard A.} and Wang, {Jen C.} and Stitzel, {Jerry A.} and Hinrichs, {Anthony L.} and Saccone, {Scott F.} and Saccone, {Nancy L.} and Bucholz, {Kathleen K.} and Cloninger, {C. Robert} and Neuman, {Rosalind J.} and Budde, {John P.} and Louis Fox and Sarah Bertelsen and John Kramer and Victor Hesselbrock and Jay Tischfield and Nurnberger, {John I.} and Laura Almasy and Bernice Porjesz and Samuel Kuperman and Schuckit, {Marc A.} and Edenberg, {Howard J.} and Rice, {John P.} and Goate, {Alison M.} and Bierut, {Laura J.}",
note = "Funding Information: The Family Study on Cocaine Dependence (FSCD) has been supported by National Institutes of Health (NIH) Grant Nos. R01 DA19963 and R01 DA013423. Analyses were partially supported by Grant No. K01 DA16618 (RAG). Genotyping services for FSCD were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to Johns Hopkins University, Contract No. HHSN268200782096C. The Collaborative Study on the Genetics of Alcoholism (COGA; co-principal investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut) includes nine centers where data collection, analysis, and storage take place. The nine sites and principal investigators and coinvestigators are as follows: University of Connecticut (V. Hesselbrock); Indiana University (H. J. Edenberg, J. Nurnberger Jr., P. M. 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 No. U10AA008401 from the NIAAA and the National Institute on Drug Abuse. ",
year = "2008",
month = dec,
day = "1",
doi = "10.1016/j.biopsych.2008.04.018",
language = "English",
volume = "64",
pages = "922--929",
journal = "Biological Psychiatry",
issn = "0006-3223",
number = "11",
}