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Cited by 215Smoking Behavior and CessationGenetic Associations and EpidemiologyNicotinic Acetylcholine Receptors Study

Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes

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Saccone, Nancy L., Saccone, Scott F., Hinrichs, Anthony L., Stitzel, Jerry A., Duan, Weimin, Pergadia, Michele L., Agrawal, Arpana, Breslau, Naomi +9 more·2009·American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
DOI 10.1002/ajmg.b.30828PMC PMC2693307
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Abstract

Tobacco smoking continues to be a leading cause of preventable death. Recent research has underscored the important role of specific cholinergic nicotinic receptor subunit (CHRN) genes in risk for nicotine dependence and smoking. To detect and characterize the influence of genetic variation on vulnerability to nicotine dependence, we analyzed 226 SNPs covering the complete family of 16 CHRN genes, which encode the nicotinic acetylcholine receptor (nAChR) subunits, in a sample of 1,050 nicotine‐dependent cases and 879 non‐dependent controls of European descent. This expanded SNP coverage has extended and refined the findings of our previous large‐scale genome‐wide association and candidate gene study. After correcting for the multiple tests across this gene family, we found significant association for two distinct loci in the CHRNA5–CHRNA3–CHRNB4 gene cluster, one locus in the CHRNB3–CHRNA6 gene cluster, and a fourth, novel locus in the CHRND–CHRNG gene cluster. The two distinct loci in CHRNA5–CHRNA3–CHRNB4 are represented by the non‐synonymous SNP rs16969968 in CHRNA5 and by rs578776 in CHRNA3, respectively, and joint analyses show that the associations at these two SNPs are statistically independent. Nominally significant single‐SNP association was detected in CHRNA4 and CHRNB1. In summary, this is the most comprehensive study of the CHRN genes for involvement with nicotine dependence to date. Our analysis reveals significant evidence for at least four distinct loci in the nicotinic receptor subunit genes that each influence the transition from smoking to nicotine dependence and may inform the development of improved smoking cessation treatments and prevention initiatives. © 2009 Wiley‐Liss, Inc.

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  • Increased risk of tobacco dependence is associated with rs6495308, rs578776, or rs1051730 in CHRNA3, and with rs1948 in CHRNB4.

    “In addition to the rs16969968 SNP in CHRNA5, there is also increased risk of tobacco dependence in individuals carrying the rs6495308, rs578776, or rs1051730 SNPs in CHRNA3 (Berrettini et al. 2008;Saccone et al. 2009), and rs1948 in CHRNB4 (Schlaepfer et al. 2008).”

    From Mechanisms of Nicotine Addiction (2021) · cites this paper as Saccone et al. 2009

    The Discussion and Conclusions (page unavailable) report an association with nicotine dependence for rs6495308 (OR 1.29), and the Results identify the major allele of rs578776 as a risk allele. The paper discusses rs1051730 as correlated with the dependence-associated locus, but gives its SNP-specific association figures for lung cancer, not tobacco dependence. The rs1948 claim is cited to Schlaepfer et al., not to this source. (LLM, conf=0.86)

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Authors
Saccone, N. L., Saccone, S. F., Hinrichs, A. L., Stitzel, J. A., Duan, W., Pergadia, M. L., Agrawal, A., Breslau, N., Grucza, R. A., Hatsukami, D., Johnson, E. O., Madden, P. A. F., Swan, G. E., Wang, J. C., Goate, A. M., Rice, J. P., & Bierut, L. J.
Affiliations
  • Washington University in St. Louis (US)
  • University of Colorado Boulder (US)
  • Michigan State University (US)
  • University of Minnesota (US)
  • RTI International (US)
  • SRI International (US)
Corresponding author
Saccone, Nancy L.
ORCID
Venue
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Publisher
Wiley
Published
2009-03-03
Volume
150B
Issue
4
Pages
453-466
ISSN
  • 1552-4841 (ISSN-L)
  • 1552-485X
DOI
10.1002/ajmg.b.30828
PMC
PMC2693307
OpenAlex
W1985349781
Cited by
215
References
52
Citations by year
2026: 2 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 7 · 2020: 5 · 2019: 3 · 2018: 9 · 2017: 5 · 2016: 16 · 2015: 20 · 2014: 12 · 2013: 27 · 2012: 28
FWCI
21.05
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Johns Hopkins University
  • National Institutes of Health
  • National Institute on Alcohol Abuse and Alcoholism (K01AA015572)
  • National Institute on Drug Abuse (R56DA012854, R01DA014369, K01DA015129, K08DA019951, R01DA012854)
  • National Human Genome Research Institute (HHSN268200782096C)
  • National Cancer Institute (P01CA089392, P01 CA89392)
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
nicotine dependence, nicotinic acetylcholine receptors, genetic susceptibility loci, single nucleotide polymorphisms, CHRNA5, CHRNA3, CHRNB4, CHRNA4, smoking, genome-wide association study, candidate gene association, smoking cessation
MeSH terms
Adult, Alleles, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Receptors, Nicotinic, Smoking, Tobacco Use Disorder, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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