The CHRNA5–A3–B4 Gene Cluster and Smoking: From Discovery to Therapeutics
Open accessAbstract
Genome-wide association studies (GWASs) have identified associations between the CHRNA5-CHRNA3-CHRNB4 gene cluster and smoking heaviness and nicotine dependence. Studies in rodents have described the anatomical localisation and function of the nicotinic acetylcholine receptors (nAChRs) formed by the subunits encoded by this gene cluster. Further investigations that complemented these studies highlighted the variability of individuals' smoking behaviours and their ability to adjust nicotine intake. GWASs of smoking-related health outcomes have also identified this signal in the CHRNA5-CHRNA3-CHRNB4 gene cluster. This insight underpins approaches to strengthen causal inference in observational data. Combining genetic and mechanistic studies of nicotine dependence and smoking heaviness may reveal novel targets for medication development. Validated targets can inform genetic therapeutic interventions for smoking cessation and tobacco-related diseases.
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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 [56]
Two variants, rs1229984 and rs16969968, have been functionally validated.
“two variants have been functionally validated (rs1229984 and rs16969968)42,43.”
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 [42]
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- Authors
- Lassi, G., Taylor, A. E., Timpson, N. J., Kenny, P. J., Mather, R. J., Eisen, T., & Munafò, M. R.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- University of Bristol (GB)
- Icahn School of Medicine at Mount Sinai (US)
- AstraZeneca (United States) (US)
- Corresponding author
- Lassi, Glenda
- Venue
- Trends in Neurosciences
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 39
- Issue
- 12
- Pages
- 851-861
- ISSN
- 0166-2236 (ISSN-L)
- PMC
- PMC5152594
- OpenAlex
- W2555564065
- Cited by
- 85
- References
- 56
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 7 · 2023: 9 · 2022: 9 · 2021: 12 · 2020: 8 · 2019: 12 · 2018: 10 · 2017: 2
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Trends in Neurosciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by-nc-nd)
- Funders
- Cancer Research UK
- British Heart Foundation
- National Institutes of Health (UL1TR001425)
- Medical Research Council (MR/K023195/1)
- National Institute on Drug Abuse (R01DA030929)
- National Center for Advancing Translational Sciences
- 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, smoking heaviness, nicotine dependence, smoking cessation, smoking-related diseases, causal inference, nicotinic receptor subunits
- MeSH terms
- Animals, Multigene Family, Humans, Receptors, Nicotinic, Smoking
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