The CHRNA5–A3–B4 Gene Cluster and Smoking: From Discovery to Therapeutics. Issue 12 (December 2016)

• Record Type: Journal Article
• Authors: Lassi, Glenda; Taylor, Amy E.; Timpson, Nicholas J.; Kenny, Paul J.; Mather, Robert J.; Eisen, Tim; Munafò, Marcus R.
• Is Part Of: Trends in neurosciences. Volume 39:Issue 12(2016)
• Page Start: 851
• Page End: 861
• Publication Date: 2016-12
• Subjects: CHRNA5–A3–B4 -- smoking behaviour -- phenotype definition -- tobacco-related disorders -- precision medicine; Neurology -- Periodicals; Neurophysiology -- Periodicals; Neurobiology -- Periodicals; 612.8
• DOI: 10.1016/j.tins.2016.10.005
• Languages: English
• ISSNs: 0166-2236

Abstract

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. Trends: Genome-wide association studies (GWASs) have highlighted genetic variants in the CHRNA5–CHRNA3–CHRB4 gene cluster associated with smoking heaviness and nicotine dependence as well as known smoking-related diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. Animal studies have described the anatomy and function of the nicotinic acetylcholine receptor (nAChR) subunits encoded by the CHRNA5–CHRNA3–CHRB4 gene cluster. More in-depth phenotyping in humans is improving our understanding of how these variants contribute to smoking behaviour. Use of this gene cluster in Mendelian randomisation analyses is enabling us to investigate the causal effects of tobacco use. The latest findings suggest that smoking heaviness could be a causal factor for schizophrenia. Validated genetic targets emerging from GWASs that influence smoking behaviour may pave the way towards individually tailored smoking cessation treatments, ultimately reducing the burden of smoking-related diseases.