Chunk #26 — From large-effect risk loci to disease biology — The CHRNA5–CHRNA3–CHRNB4 nicotinic receptor gene cluster and the CYP2A6 nicotine-metabolising gene.
Nicotine is the primary addictive compound among the complex mixture in tobacco smoke. The addictive effect of nicotine is considered to be due to its binding of the nicotinic acetylcholine receptors (nAChRs)56. Ligand-gated ion channels (including these) are widely distributed in the nervous system where they modulate the release of several neurotransmitters, including dopamine, gamma-aminobutyric acid, and glutamate57. Variants mapped to genes encoding nAChR subunits (specifically, the CHRNA5–CHRNA3–CHRNB4 gene cluster) were identified as associated with nicotine dependence in a candidate-gene study58. The initial findings were replicated and expanded by numerous subsequent analyses, also including large-scale GWAS15. Multiple variants causing coding changes in the protein products of CHRNA5, CHRNA3, and CHRNB4 were confirmed as associated with a wide range of traits related to tobacco smoking, such as nicotine dependence, smoking severity and heaviness, smoking cessation, and nicotine aversive effects59. Beyond the association with smoking behaviours, CHRNA5–CHRNA3–CHRNB4 variants showed associations with harmful downstream consequences of tobacco smoking, including lung cancer, chronic obstructive pulmonary disease, and reduced pulmonary function60, 61.
