From Men to Mice: CHRNA5/CHRNA3, Smoking Behavior and Disease
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INTRODUCTION: The nicotinic acetylcholine receptor (nAChR) gene cluster CHRNA5-A3-B4 on chromosome 15 has been the subject of a considerable body of research over recent years. Two highly correlated single nucleotide polymorphisms (SNPs) within this region--rs16969968 in CHRNA5 and rs1051730 in CHRNA3--have generated particular interest. METHODS: We reviewed the literature relating to SNPs rs16969968 and rs1051730 and smoking-related phenotypes, and clinical and preclinical studies, which shed light on the mechanisms underlying these associations. RESULTS: Following the initial discovery of an association between this locus and smoking behavior, further associations with numerous phenotypes have been subsequently identified, including smoking-related behaviors, diseases, and cognitive phenotypes. Potential mechanisms thought to underlie these have also been described, as well as possible gene × environment interaction effects. CONCLUSIONS: Perhaps counter to the usual route of scientific inquiry, these initial findings, based exclusively on human samples and strengthened by their identification through agnostic genome-wide methods, have led to preclinical research focused on determining the mechanism underlying these associations. Progress has been made using knockout mouse models, highlighting the importance of α5 nAChR subunits in regulating nicotine intake, particularly those localized to the habenula-interpeduncular nucleus pathway. Translational research seeking to evaluate the effect of nicotine challenge on brain activation as a function of rs16969968 genotype using neuroimaging technologies is now called for, which may point to new targets for novel smoking cessation therapies.
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CHRNA5 has been linked in several studies to smoking and various smoking risk factors.
“CHRNA5 has been linked in several studies to smoking and various smoking risk factors [53–57].”
From Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes (2022) · cites this paper as [53]
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Chen, D., Truong, T., Gaborieau, V., Byrnes, G. B., Chabrier, A., Chuang, S.-C., Olshan, A. F., Weissler, M. C., Luo, J., Romkes, M., et al. (2011) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-10-1008 · Cited by 21 · see citing works
Chromosome 15q24-25.1 variants, diet, and lung cancer susceptibility in cigarette smokers
Sakoda, L. C., Loomis, M. M., Doherty, J. A., Neuhouser, M. L., Barnett, M. J., Thornquist, M. D., Weiss, N. S., Goodman, G. E., & Chen, C. (2011) · Cancer Causes & Control · doi:10.1007/s10552-010-9716-1 · Cited by 20 · see citing works
Forum: the case for gene–environment interactions in psychiatry
Uher, R. (2008) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e328306a7b9 · Cited by 20 · see citing works
Combined analysis of CHRNA5 , CHRNA3 and CYP2A6 in relation to adolescent smoking behaviour
Rodrı́guez, S., Cook, D. G., Gaunt, T. R., Nightingale, C. M., Whincup, P. H., & Day, I. N. M. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111405352 · Cited by 17 · see citing works
Association of smoking with tumor size at diagnosis in non-small cell lung cancer
Chen, X., Gorlov, I. P., Merriman, K. W., Weng, S., Foy, M., Keener, G., Amos, C. I., Spitz, M. R., Kimmel, M., & Gorlova, O. Y. (2011) · Lung Cancer · doi:10.1016/j.lungcan.2011.04.020 · Cited by 15 · see citing works
Sorice, R., Bione, S., Sansanelli, S., Ulivi, S., Athanasakis, E., Lanzara, C., Nutile, T., Sala, C. F., Camaschella, C., D’Adamo, P., et al. (2011) · European Journal of Human Genetics · doi:10.1038/ejhg.2010.240 · Cited by 15 · see citing works
Marques-Vidal, P. M., Kutalik, Z., Paccaud, F., Bergmann, S., Waeber, G., Vollenweider, P., & Cornuz, J. (2011) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntr084 · Cited by 12 · see citing works
Commentary on ‘The case for gene–environment interactions in psychiatry’
Riley, B. P. (2008) · Current Opinion in Psychiatry · doi:10.1097/01.yco.0000320757.22733.30 · Cited by 9 · see citing works
Susceptibility Locus for Lung Cancer at 15q25.1 Is Not Associated With Risk of Pancreatic Cancer
Chen, J., Wu, X., Pande, M., Amos, C. I., Killary, A. M., Sen, S., & Frazier, M. L. (2011) · Pancreas · doi:10.1097/mpa.0b013e318219dafe · Cited by 9 · see citing works
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The association of cigarette smoking with depression and anxiety: a systematic review
Fluharty, M., Taylor, A. E., Grabski, M., & Munafò, M. R. (2017) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntw140 · Cited by 1,299 · see citing works
Self-citationTaylor, A. E., Fluharty, M. E., Bjørngaard, J. H., Gabrielsen, M. E., Skorpen, F., Marioni, R. E., Campbell, A., Engmann, J., Mirza, S. S., Loukola, A., et al. (2014) · BMJ Open · doi:10.1136/bmjopen-2014-006141 · Cited by 187 · see citing works
Self-citationCausal Inference in Developmental Origins of Health and Disease (DOHaD) Research
Gage, S. H., Munafò, M. R., & Davey Smith, G. (2016) · Annual Review of Psychology · doi:10.1146/annurev-psych-122414-033352 · Cited by 173 · see citing works
Self-citationA rare missense mutation in CHRNA4 associates with smoking behavior and its consequences
Thorgeirsson, T. E., Steinberg, S., Reginsson, G. W., Bjornsdottir, G., Rafnar, T., Jonsdottir, I., Helgadottir, A., Gretarsdottir, S., Helgadottir, H., Jonsson, S., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.13 · Cited by 33 · see citing works
Using Mendelian randomisation to infer causality in depression and anxiety research
Gage, S. H., Smith, G. D., Zammit, S., Hickman, M., & Munafò, M. R. (2013) · Depression and Anxiety · doi:10.1002/da.22150 · Cited by 32 · see citing works
Self-citationDannemann, M., Milaneschi, Y., Yermakovich, D., Stiglbauer, V., Kariis, H. M., Krebs, K., Friese, M. A., Otte, C., Estonian Biobank Research Team, Esko, T., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02196-2 · Cited by 23 · see citing works
- Authors
- Ware, J. J., van den Bree, M., & Munafò, M. R.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Ware, Jennifer J.
- ORCID
- Ware, Jennifer J.
- Venue
- Nicotine & Tobacco Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-04-27
- Volume
- 14
- Issue
- 11
- Pages
- 1291-1299
- ISSN
- 1462-2203 (ISSN-L)
- 1469-994X
- PMC
- PMC3482013
- OpenAlex
- W2128772060
- Cited by
- 62
- References
- 88
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 8 · 2015: 8 · 2014: 13 · 2013: 6
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Nicotine & Tobacco Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- British Heart Foundation
- Medical Research Council
- Economic and Social Research Council
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- nicotinic acetylcholine receptors, CHRNA5, CHRNA3, rs16969968, rs1051730, smoking behavior, nicotine use, gene-environment interaction, knockout mouse models, smoking cessation, cognitive phenotypes
- MeSH terms
- Alcoholism, Animals, Behavior, Female, Humans, Lung Neoplasms, Male, Nerve Tissue Proteins, Phenotype, Receptors, Nicotinic, Smoking, Tobacco Use Disorder, Substance-Related Disorders, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Mice, Gene-Environment Interaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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