One of the strongest findings in SUD genetics pertains to nicotine use — the relationship between markers mapped to the gene cluster encoding neuronal acetylcholine receptor (CHRNA3–CHRNA5–CHRNB4) and smoking heaviness or dependence21–23. These genes encode cholinergic nicotinic receptor alpha 3 and 5 and beta 4 subunits and their protein products interact directly with nicotine. We review the functional consequences of genetic variation in the CHRNA3–CHRNA5–CHRNB4 gene cluster in the section “From large-effect risk loci to disease biology”. There have been comparatively many large-scale GWAS studies of behaviours related to cigarette smoking; the largest to date is, as for alcohol use, GSCAN15, which considered up to 1.2 million subjects for “smoking initiation” and hundreds of thousands for several other smoking phenotypes including cigarettes per day (where the lead variant mapped to CHRNA5 with P = 1.2×10−278) and smoking cessation. These phenotypes, however, relate mostly to quantity and frequency of use, rather than nicotine dependence; cessation and initiation of use, while very important clinically, are also different from dependence. This study was well-powered and identified remarkably many significant risk loci, e.g. 378 independent loci for smoking initiation.
