| Title: | Rare coding variants in CHRNB2 reduce the likelihood of smoking |
| Journal: | Nature Genetics |
| Published: | 12 Jul 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37308787/ |
| DOI: | https://doi.org/10.1038/s41588-023-01417-8 |
| URL: | https://www.nature.com/articles/s41588-023-01417-8 |
Publication 21
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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.42 Authors
- Veera M Rajagopal
- Kyoko Watanabe
- Joelle Mbatchou
- Ariane Ayer
- Peter Quon
- Deepika Sharma
- Michael D Kessler
- Kavita Praveen
- Sahar Gelfman
- Neelroop Parikshak
- Jacqueline M Otto
- Suying Bao
- Shek Man Chim
- Elias Pavlopoulos
- Andreja Avbersek
- Manav Kapoor
- Esteban Chen
- Marcus B Jones
- Michelle Leblanc
- Jonathan Emberson
- Rory Collins
- Jason Torres
- Pablo Kuri Morales
- Roberto Tapia-Conyer
- Jesus Alegre
- Jaime Berumen
- GHS-REGN DiscovEHR collaboration
- Regeneron Genetics Center
- Alan R Shuldiner
- Suganthi Balasubramanian
- Gonçalo Abecasis
- Hyun M Kang
- Jonathan Marchini
- Eli A Stahl
- Eric Jorgenson
- Robert Sanchez
- Wolfgang Liedtke
- Matthew Anderson
- Michael Cantor
- David Lederer
- Aris Baras
- Giovanni Coppola