Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior
Open accessAbstract
Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).
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Sequence variants linked to smoking behavior are located in regions containing the CHRNB3-CHRNA6 genes on chromosome 8p11.
“While sequence variants associated with smoking behavior lie within the regions that harbor the CHRNB3-CHRNA6 genes on chromosome 8p11 (Thorgeirsson et al. 2010)”
From Nicotine Withdrawal (2015) · cites this paper as Thorgeirsson et al. 2010
Gene discovery for tobacco and alcohol use has been difficult.
“They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6–11.”
From Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use (2019) · cites this paper as [7]
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- Authors
- The ENGAGE Consortium, Thorgeirsson, T. E., Gudbjartsson, D. F., Surakka, I., Vink, J. M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., Mangino, M., Prokopenko, I., Mägi, R., Keskitalo, K., Gudjonsdottir, I. H., Gretarsdottir, S., Stefansson, H., Thompson, J. R., Aulchenko, Y. S., Nelis, M., Aben, K. K., den Heijer, M., Dirksen, A., Ashraf, H., Soranzo, N., Valdes, A. M., Steves, C., Uitterlinden, A. G., Hofman, A., Tönjes, A., Kovacs, P., Hottenga, J. J., Willemsen, G., Vogelzangs, N., Döring, A., Dahmen, N., Nitz, B., Pergadia, M. L., Saez, B., De Diego, V., Lezcano, V., Garcia-Prats, M. D., Ripatti, S., Perola, M., Kettunen, J., Hartikainen, A.-L., Pouta, A., Laitinen, J., Isohanni, M., Huei-Yi, S., Allen, M., Krestyaninova, M., Hall, A. S., Jones, G. T., van Rij, A. M., Mueller, T., Dieplinger, B., Haltmayer, M., Jonsson, S., Matthiasson, S. E., Oskarsson, H., Tyrfingsson, T., Kiemeney, L. A., Mayordomo, J. I., Lindholt, J. S., Pedersen, J. H., Franklin, W. A., Wolf, H., Montgomery, G. W., Heath, A. C., Martin, N. G., Madden, P. A. F., Giegling, I., Rujescu, D., Järvelin, M.-R., Salomaa, V., Stumvoll, M., Spector, T. D., Wichmann, H.-E., Metspalu, A., Samani, N. J., Penninx, B. W., Oostra, B. A., Boomsma, D. I., Tiemeier, H., van Duijn, C. M., Kaprio, J., Gulcher, J. R., McCarthy, M. I., Peltonen, L., Thorsteinsdottir, U., & Stefansson, K.
- Affiliations
- deCODE Genetics (Iceland) (IS)
- University of Helsinki (FI)
- Vrije Universiteit Amsterdam (NL)
- Erasmus MC (NL)
- Estonian Biocentre (EE)
- Helmholtz Munich (DE)
- St Thomas' Hospital (GB)
- Centre for Human Genetics (GB)
- University of Leicester (GB)
- Radboud University Medical Center (NL)
- Gentofte Hospital (DK)
- Leipzig University (DE)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Johannes Gutenberg University Mainz (DE)
- Washington University in St. Louis (US)
- Hospital San Pedro (ES)
- Finnish Institute for Health and Welfare (FI)
- Wellcome Sanger Institute (GB)
- University of Oulu (FI)
- Finnish Institute of Occupational Health (FI)
- University of Oxford (GB)
- European Bioinformatics Institute (GB)
- University of Leeds (GB)
- University of Otago (NZ)
- Convent Hospital of the Brothers of Saint John of God (AT)
- Universidad de Zaragoza (ES)
- Regionshospitalet Viborg (DK)
- University of Copenhagen (DK)
- University of Colorado Denver (US)
- Colorado School of Public Health (US)
- QIMR Berghofer Medical Research Institute (AU)
- Ludwig-Maximilians-Universität München (DE)
- Imperial College London (GB)
- ORCID
- Thorgeirsson, Thorgeir E
- Gudbjartsson, Daniel F
- Surakka, Ida
- Vink, Jacqueline M
- Amin, Najaf
- Geller, Frank
- Sulem, Patrick
- Esko, Tõnu
- Walter, Stefan
- Gieger, Christian
- Rawal, Rajesh
- Mangino, Massimo
- Prokopenko, Inga
- Mägi, Reedik
- Gudjonsdottir, Iris H
- Aulchenko, Yurii S
- Nelis, Mari
- Aben, Katja K
- Ashraf, Haseem
- Soranzo, Nicole
- Valdes, Ana M
- Steves, Claire
- Uitterlinden, André G
- Tönjes, Anke
- Kovacs, Peter
- Hottenga, Jouke Jan
- Willemsen, Gonneke
- Vogelzangs, Nicole
- Nitz, Barbara
- Ripatti, Samuli
- Perola, Markus
- Kettunen, Johannes
- Pouta, Anneli
- Laitinen, Jaana
- Isohanni, Matti
- Krestyaninova, Maria
- Hall, Alistair S
- Jones, Gregory T
- Mueller, Thomas
- Kiemeney, Lambertus A
- Mayordomo, Jose I
- Lindholt, Jes S
- Pedersen, Jesper Holst
- Montgomery, Grant W
- Heath, Andrew C
- Martin, Nicholas G
- Madden, Pamela A F
- Giegling, Ina
- Rujescu, Dan
- Järvelin, Marjo-Riitta
- Salomaa, Veikko
- Spector, Tim D
- Wichmann, H-Erich
- Metspalu, Andres
- Samani, Nilesh J
- Penninx, Brenda W
- Boomsma, Dorret I
- Tiemeier, Henning
- Kaprio, Jaakko
- McCarthy, Mark I
- Peltonen, Leena
- Venue
- Nature Genetics
- Published
- 2010-04-25
- Volume
- 42
- Issue
- 5
- Pages
- 448-453
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3080600
- OpenAlex
- W2103465143
- Cited by
- 689
- References
- 37
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 6 · 2023: 17 · 2022: 22 · 2021: 23 · 2020: 24 · 2019: 39 · 2018: 37 · 2017: 51 · 2016: 73 · 2015: 64 · 2014: 71 · 2013: 67 · 2012: 80
- FWCI
- 51.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- VU Research Portal (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Site cant be reached (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Wellcome Trust (079771, 072856, 089061)
- European Commission (LSHM‐CT2004‐005166, 201413)
- National Institutes of Health
- National Institute on Drug Abuse (R01DA017932)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- smoking behavior, cigarettes per day, smoking initiation, CHRNA6, CYP2A6, CYP2B6, nicotinic acetylcholine receptors, nicotine metabolism, nicotine dependence, 19q13, lung cancer risk, genetic association
- MeSH terms
- Alleles, Aryl Hydrocarbon Hydroxylases, Female, Humans, Lung Neoplasms, Male, Phenotype, Receptors, Nicotinic, Smoking, Tobacco Use Disorder, Genetic Variation, Cohort Studies, Odds Ratio, Genomics, Genome-Wide Association Study, Cytochrome P-450 CYP2A6
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