Journal article
Rare coding variants in CHRNB2 reduce the likelihood of smoking
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, pdf, 4.1MB, Terms of use)
-
- Publisher copy:
- 10.1038/s41588-023-01417-8
Authors
Contributors
+ GHS-REGN DiscovEHR collaboration
- Role:
- Contributor
+ Regeneron Genetics Center
- Role:
- Contributor
- Publisher:
- Springer Nature
- Journal:
- Nature Genetics More from this journal
- Volume:
- 55
- Issue:
- 7
- Pages:
- 1138-1148
- Publication date:
- 2023-06-12
- Acceptance date:
- 2023-05-04
- DOI:
- EISSN:
-
1546-1718
- ISSN:
-
1061-4036
- Language:
-
English
- Keywords:
- Pubs id:
-
1344569
- Local pid:
-
pubs:1344569
- Deposit date:
-
2023-05-24
- ARK identifier:
Terms of use
- Copyright holder:
- Rajagopal et al.
- Copyright date:
- 2023
- Rights statement:
- © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record