Journal Article

Rare coding variants in CHRNB2 reduce the likelihood of smoking

Kapoor, Manav, Rajagopal, Veera M., Shuldiner, Alan R., Abecasis, Gonçalo R., Lederer, David, Emberson, Jonathan, Chen, Esteban, Otto, Jacqueline M., Stahl, Eli A., Berumen, Jaime, Bao, Suying, Coppola, Giovanni, Watanabe, Kyoko, Chim, Shek Man, Cantor, Michael, Morales, Pablo Kuri, Torres, Jason, Praveen, Kavita, Ayer, Ariane, Kang, Hyun M., Balasubramanian, Suganthi, Mbatchou, Joelle, Liedtke, Wolfgang, Sharma, Deepika, Jones, Marcus B., Parikshak, Neelroop, Quon, Peter, Leblanc, Michelle, Baras, Aris, Sanchez, Robert, Anderson, Matthew, Marchini, Jonathan, Gelfman, Sahar, Jorgenson, Eric, Kessler, Michael D., Avbersek, Andreja, Tapia-Conyer, Roberto, Pavlopoulos, Elias, Collins, Rory, Alegre, Jesus

2023

Overview

Human genetic studies of smoking behavior have been thus far largely limited to common variants. Studying rare coding variants has the potential to identify drug targets. We performed an exome-wide association study of smoking phenotypes in up to 749,459 individuals and discovered a protective association in CHRNB2 , encoding the β2 subunit of the α4β2 nicotine acetylcholine receptor. Rare predicted loss-of-function and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking heavily (odds ratio (OR) = 0.65, confidence interval (CI) = 0.56–0.76, P  = 1.9 × 10 −8 ). An independent common variant association in the protective direction ( rs2072659 ; OR = 0.96; CI = 0.94–0.98; P  = 5.3 × 10 −6 ) was also evident, suggesting an allelic series. 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. An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/22 / 45/23 / 45/43 / 45/56 / 631/154 / 631/208/1515 / 631/208/457 / Addictions / Agriculture / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Chronic obstructive pulmonary disease / Drug self-administration / Gene Function / Genealogy / Genes / Genomes / Genotype & phenotype / Health behavior / Human Genetics / Humans / Mice / Neural coding / Nicotine / Odds Ratio / Phenotype / Phenotypes / Smoking / Smoking - genetics / Target recognition / Therapeutic targets / Tobacco Use Disorder - genetics