Rare coding variants inCHRNB2reduce the likelihood of smoking

Abstract

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 β2 subunit of α4β2 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. α4β2 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 β2 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.

Genetic associations of protein-coding variants in venous thromboembolism

“…Notably, effect sizes for identified genes from collapsing analysis are lower than expected from previous studies. Considering that HR estimates from subsequent survival analysis were larger and more consistent with previous reports, we hypothesize that the comparatively smaller effect sizes observed during the initial gene discovery phase were primarily due to the usage of saddle point-approximationcorrected logistic mixed-model approach implemented in the SAIGE-GENE+ software, which might yield slightly conservative effect estimates, particularly when assessing significance for binary traits with imbalanced case-control ratios 39 .…”

Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample

“…Most recently, in a large sample of both current and former smokers (~ 110K) and never smokers (~ 375K), an exome-wide association study (ExWAS) showed that rare predicted loss-of-function and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds (protective) for smoking more than 10 cigarettes per day. An independent common variant of CHRNB2 , rs2072659, also showed a protective effect for heavy smoking 33 .…”

Drug development advances in human genetics‐based targets

“…In a WES of smoking phenotypes in up to 749,459 individuals, Rajagopal et al 305 found that LOF mutations in CHRNB2, encoding the β2 subunit of the α4β2 nicotinic acetylcholine receptor, were associated with a 35% lower risk of heavy smoking. Darrah et al 306 found by GWAS that AGTR2 deletion or antagonism prevented pulmonary cystic fibrosis and is expected to be a novel therapeutic target for pulmonary cystic fibrosis.…”

“…A few examples of relevant targets are given below. In a WES of smoking phenotypes in up to 749,459 individuals, Rajagopal et al 305 . found that LOF mutations in CHRNB2 , encoding the β2 subunit of the α4β2 nicotinic acetylcholine receptor, were associated with a 35% lower risk of heavy smoking.…”