In:
Nature Genetics, Springer Science and Business Media LLC, Vol. 55, No. 7 ( 2023-07), p. 1138-1148
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.
Type of Medium:
Online Resource
ISSN:
1061-4036
,
1546-1718
DOI:
10.1038/s41588-023-01417-8
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2023
detail.hit.zdb_id:
1494946-5
SSG:
12
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