Rare coding variants in CHRNB2 reduce the likelihood of smoking

Human genetic studies of smoking behavior have been so far largely limited to common variations. Studying rare coding variants has potential to identify new drug targets and refine our understanding of the mechanisms of known targets. We performed an exome-wide association study (ExWAS) of smoking phenotypes in up to 749,459 individuals across multiple ancestries and discovered a protective association signal in CHRNB2 that encodes the {beta}2 subunit of 4{beta}2 nicotine acetylcholine receptor (nAChR). Rare predicted loss-of-function (pLOF) and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking more than 10 cigarettes per day (OR=0.65, CI=0.56-0.76, P=1.9e-8). An independent common variant association in the protective direction (rs2072659; OR=0.96; CI=0.94-0.98; P=5.3e-6) was also evident, suggesting an allelic series. The protective effects of both rare and common variants were detectable to some extent on phenotypes downstream of smoking including lung function, emphysema, chronic obstructive pulmonary disease (COPD) and lung cancer. 4{beta}2 is the predominant nAChR in human brain and is one of the targets of varenicline, a partial nAChR agonist/antagonist used to aid smoking cessation. Our findings in humans align with decades-old experimental observations in mice that {beta}2 loss abolishes nicotine mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction.