title: The CHRNA5-A3-B4 Gene Cluster and Smoking: From Discovery to Therapeutics.
abstract: 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.
authors.affiliation: UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK; Oncology Translational Medicine Unit, Early Clinical Development, AstraZeneca, Cambridge, UK. Electronic address: glenda.lassi@bristol.ac.uk.
authors.forename: Glenda
authors.initials: G
authors.lastname: Lassi
authors.affiliation: UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Taylor
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Department of Neuroscience and Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
authors.affiliation: Neuroscience iMED, AstraZeneca, Cambridge, MA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mather
authors.affiliation: Oncology Translational Medicine Unit, Early Clinical Development, AstraZeneca, Cambridge, UK; Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Eisen
authors.affiliation: UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Munafò
mesh_terms: D000818:Animals; D006801:Humans; D005810:Multigene Family; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000188:drug therapy / Q000235:genetics*
chemical_list: D011978:Receptors, Nicotinic
keywords: CHRNA5–A3–B4; phenotype definition; precision medicine; smoking behaviour; tobacco-related disorders