Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs
Open accessAbstract
Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.
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Allelic variation in the α5/α3/β4 nAChR subunit gene cluster at chromosome 15q25 significantly increases risk of tobacco addiction.
“It has been shown that allelic variation in the α5/α3/β4 nAChR subunit gene cluster located in chromosome region 15q25 significantly increases risk of tobacco addiction (Saccone et al. 2007;Berrettini et al. 2008;Lips et al. 2010).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Saccone et al. 2007
The most compelling evidence for risk variants contributing to smoking behavior was in the CHRNA5/A3/B4 gene cluster, which encodes the α5, α3, and β4 subunits.
“The most compelling evidence for risk variants contributing to smoking behavior was in the CHRNA5/A3/B4 gene cluster, which encodes the α5, α3, and β4 subunits.”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [91]
The most thoroughly investigated and replicated finding to date is the association with rs16969968 in CHRNA5.
“The most thoroughly investigated and replicated finding to date is the association with rs16969968, in CHRNA5 (91).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [91]
SNP rs578776 is strongly associated with nicotine dependence and has a low correlation with rs16969968 (r2 = 0.18), indicating that it represents a statistically independent signal.
“A second signal in the CHRNA5/A3/B4 cluster is tagged by SNP rs578776; it is strongly associated with nicotine dependence and has a low correlation with rs16969968 (r2 = 0.18), indicating that it represents a statistically independent signal (90,91).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [91]
Initiation of smoking behavior and transition to dependence has been found to show strong heritability, with reported heritability coefficients ranging from 30% to greater than 80% (mean approximately 60% for initiation and 70% for progression to dependence).
“With regard to the latter factors, initiation of smoking behavior and transition to dependence (i.e. persistent smoking) has been found to show strong heritability (60). The reported heritability coefficients range from 30% to greater than 80% (a mean of approximately 60% for initiation and 70% for progression to dependence).”
From Tobacco addiction (2008) · cites this paper as [60]
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- Authors
- Saccone, S. F., Hinrichs, A. L., Saccone, N. L., Chase, G. A., Konvicka, K., Madden, P. A. F., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O., Swan, G. E., Goate, A. M., Rutter, J., Bertelsen, S., Fox, L., Fugman, D., Martin, N. G., Montgomery, G. W., Wang, J. C., Ballinger, D. G., Rice, J. P., & Bierut, L. J.
- Affiliations
- Washington University in St. Louis (US)
- Pennsylvania State University (US)
- Perlegen (United States) (US)
- Michigan State University (US)
- RTI International (US)
- University of Minnesota (US)
- University of Michigan (US)
- SRI International (US)
- National Institute on Drug Abuse (US)
- Rutgers, The State University of New Jersey (US)
- QIMR Berghofer Medical Research Institute (AU)
- Corresponding author
- Saccone, Scott F.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-11-29
- Volume
- 16
- Issue
- 1
- Pages
- 36-49
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2270437
- OpenAlex
- W2118320202
- Cited by
- 850
- References
- 48
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 12 · 2023: 20 · 2022: 16 · 2021: 24 · 2020: 65 · 2019: 37 · 2018: 35 · 2017: 35 · 2016: 54 · 2015: 51 · 2014: 48 · 2013: 58 · 2012: 86
- FWCI
- 31.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute on Drug Abuse (R56DA012854, DA12854, DA015129, N01DA07079, K01DA015129, R01DA012854)
- National Cancer Institute (CA89392, P01CA089392)
- 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, CHRNA5, single nucleotide polymorphisms, genetic association, genetic susceptibility loci, recessive inheritance, KCNJ6, GABRA4, smoking, Fagerström Test for Nicotine Dependence
- MeSH terms
- Adult, Aged, Aged, 80 and over, Chromosomes, Human, Pair 8, Female, Genetic Markers, Genotype, Humans, Male, Middle Aged, Receptors, Nicotinic, Tobacco Use Disorder, Genetic Variation, Cluster Analysis, Case-Control Studies, Polymorphism, Single Nucleotide
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