Rare coding variants in CHRNB2 reduce the likelihood of smoking

GHS-REGN DiscovEHR collaboration, Regeneron Genetics Center, RGC Management & Leadership Team, Sequencing & Lab Operations, Clinical Informatics, Genome Informatics & Data Engineering, Analytical Genetics and Data Science, Therapeutic Area Genetics, Research Program Management & Strategic Initiatives, Strategic Partnerships & Business Operations

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1138-1148
Number of pages11
JournalNature Genetics
Volume55
Issue number7
DOIs
StatePublished - Jul 2023

All Science Journal Classification (ASJC) codes

  • Genetics

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