| Title: | Rare coding variants in CHRNB3 associate with reduced daily cigarette smoking across ancestries |
| Journal: | Nature Communications |
| Published: | 24 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41735279/ |
| DOI: | https://doi.org/10.1038/s41467-026-68825-2 |
| URL: | http://dx.doi.org/10.1038/s41467-026-68825-2 |
Publication 17647
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Abstract
Rare coding variants that alter protein function and confer beneficial health effects can suggest potential drug targets. CHRNB3 encodes the β3 subunit of nicotinic acetylcholine receptors that bind nicotine and mediate its action in the brain. Here we report an exome-wide association study of number of cigarettes smoked per day (cig per day) in 37,897 current smokers from the Mexico City Prospective Study. We identify a deleterious missense variant in CHRNB3, p.Glu284Gly, that associates with a significant reduction in daily cigarette consumption. The missense variant is enriched in people of Indigenous Mexican ancestry but rare in other ancestries. We further identify a predicted loss-of-function variant in CHRNB3 that significantly associates with reduction in number of smoked cigarettes per day in participants of Japan Biobank. This variant is enriched in people of East Asian ancestry but is rare in other ancestries. Finally, we find that rare deleterious missense and predicted loss-of-function variants in aggregate associate with a reduction in the number of smoked cigarettes per day in individuals of European ancestry from the UK Biobank. Our results suggest that loss of function of CHRNB3 significantly associates with daily cigarette smoking, proposing β3 inhibition as a potential therapeutic strategy for nicotine addiction.</p>
13 Keywords
- Adult
- Cigarette Smoking
- Female
- Genome-Wide Association Study
- Humans
- Japan
- Male
- Mexico
- Middle Aged
- Mutation, Missense
- Prospective Studies
- Receptors, Nicotinic
- White People
27 Authors
- Veera M. Rajagopal
- Andrey Ziyatdinov
- Tyler Joseph
- Ariane Ayer
- Mohsin Ahmed
- Joelle Mbatchou
- Yuxin Zou
- Amelia J. Averitt
- Nilanjana Banerjee
- Michael Cantor
- Jason M. Torres
- Esteban Chen
- Jennifer Rico Varela
- Marcus Jones
- John Overton
- Olivier Harari
- Luca Lotta
- Gonçalo Abecasis
- Aris Baras
- Jaime Berumen
- Pablo Kuri-Morales
- Jesús Alegre-Díaz
- Roberto Tapia-Conyer
- Rory Collins
- Jonathan R. Emberson
- Jonathan Marchini
- Giovanni Coppola
1 Application
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
Enabling scientific discoveries that improve human health