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Cited by 152Smoking Behavior and CessationGenetic Associations and EpidemiologyNicotinic Acetylcholine Receptors Study

A Risk Allele for Nicotine Dependence in CHRNA5 Is a Protective Allele for Cocaine Dependence

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Grucza, Richard A., Wang, Jen C., Stitzel, Jerry A., Hinrichs, Anthony L., Saccone, Scott F., Saccone, Nancy L., Bucholz, Kathleen K., Cloninger, C. Robert +16 more·2008·Biological Psychiatry
DOI 10.1016/j.biopsych.2008.04.018PMC PMC2582594
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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.

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  • The rs16969968 risk variant is associated with heavy smoking, early onset of smoking behavior, and a pleasurable buzz from tobacco.

    “The rs16969968 risk variant is associated with heavy smoking (Berrettini et al. 2008;Bierut et al. 2008;Grucza et al. 2008;Stevens et al. 2008), early onset of smoking behavior (Weiss et al. 2008), and with a”

    From Mechanisms of Nicotine Addiction (2021) · cites this paper as Grucza et al. 2008

  • The association with rs16969968 has been replicated either directly or using highly correlated SNPs by several groups.

    “This association has been replicated either directly or using highly correlated SNPs by several groups (92–97).”

    From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [97]

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Research works printed but not linked: 2

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4. Washington, D.C: American Psychiatric Association; 2000. Fourth Edition Text Revision
  2. Grucza RA, Bierut LJ. Update on COGA findings: Co-occurring risk factors for alcohol dependence and habitual smoking. Alcohol Res Health. 2006In Press

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Authors
Grucza, R. A., Wang, J. C., Stitzel, J. A., Hinrichs, A. L., Saccone, S. F., Saccone, N. L., Bucholz, K. K., Cloninger, C. R., Neuman, R. J., Budde, J. P., Fox, L., Bertelsen, S., Kramer, J., Hesselbrock, V., Tischfield, J., Nurnberger, J. I., Almasy, L., Porjesz, B., Kuperman, S., Schuckit, M. A., Edenberg, H. J., Rice, J. P., Goate, A. M., & Bierut, L. J.
Affiliations
  • Washington University in St. Louis (US)
  • University of Colorado Boulder (US)
  • University of Iowa (US)
  • UConn Health (US)
  • Rutgers, The State University of New Jersey (US)
  • Texas Biomedical Research Institute (US)
  • University of California San Diego (US)
  • Indiana University School of Medicine (US)
Corresponding author
Grucza, Richard A.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2008-12
Volume
64
Issue
11
Pages
922-929
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2008.04.018
PMC
PMC2582594
OpenAlex
W2035924724
Cited by
152
References
44
Citations by year
2026: 1 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 4 · 2021: 3 · 2020: 10 · 2019: 1 · 2018: 4 · 2017: 8 · 2016: 8 · 2015: 13 · 2014: 11 · 2013: 12 · 2012: 18
FWCI
9.93
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • State University of New York
  • Washington University in St. Louis
  • University of Connecticut
  • Johns Hopkins University (HHSN268200782096C)
  • National Institutes of Health (HHSN268200782096C)
  • SUNY Downstate Medical Center
  • National Institute on Alcohol Abuse and Alcoholism (U10AA008401)
  • National Institute on Drug Abuse (K01DA16618, R01 DA19963, R01DA019963, R01DA013423, HHSN268200782096C, K01DA016618, DA013423)
  • National Human Genome Research Institute (HHSN268200782096C)
Topics
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
CHRNA5, rs16969968, nicotine dependence, cocaine dependence, nicotinic acetylcholine receptors, non-synonymous polymorphisms, genetic association, protective alleles, dopamine reward pathway, habitual smoking
MeSH terms
Adolescent, Adult, Alcoholism, Family Health, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Nerve Tissue Proteins, Receptors, Nicotinic, Risk Factors, Tobacco Use Disorder, Genetic Variation, Multivariate Analysis, Confidence Intervals, Chi-Square Distribution, Odds Ratio, Case-Control Studies, Cocaine-Related Disorders, Genetic Predisposition to Disease, Young Adult

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