TY - JOUR
T1 - Rare coding variants in CHRNB2 reduce the likelihood of smoking
AU - GHS-REGN DiscovEHR collaboration
AU - Regeneron Genetics Center
AU - RGC Management & Leadership Team
AU - Sequencing & Lab Operations
AU - Clinical Informatics
AU - Genome Informatics & Data Engineering
AU - Analytical Genetics and Data Science
AU - Therapeutic Area Genetics
AU - Research Program Management & Strategic Initiatives
AU - Strategic Partnerships & Business Operations
AU - Rajagopal, Veera M.
AU - Watanabe, Kyoko
AU - Mbatchou, Joelle
AU - Ayer, Ariane
AU - Quon, Peter
AU - Sharma, Deepika
AU - Kessler, Michael D.
AU - Praveen, Kavita
AU - Gelfman, Sahar
AU - Parikshak, Neelroop
AU - Otto, Jacqueline M.
AU - Bao, Suying
AU - Chim, Shek Man
AU - Pavlopoulos, Elias
AU - Avbersek, Andreja
AU - Kapoor, Manav
AU - Chen, Esteban
AU - Jones, Marcus B.
AU - Leblanc, Michelle
AU - Emberson, Jonathan
AU - Collins, Rory
AU - Torres, Jason
AU - Morales, Pablo Kuri
AU - Tapia-Conyer, Roberto
AU - Alegre, Jesus
AU - Berumen, Jaime
AU - Adams, Lance J.
AU - Blank, Jackie
AU - Bodian, Dale
AU - Boris, Derek
AU - Buchanan, Adam
AU - Carey, David J.
AU - Colonie, Ryan D.
AU - Davis, F. Daniel
AU - Hartzel, Dustin N.
AU - Kelly, Melissa
AU - Kirchner, H. Lester
AU - Leader, Joseph B.
AU - Ledbetter, David H.
AU - Manus, J. Neil
AU - Martin, Christa L.
AU - Metpally, Raghu P.
AU - Meyer, Michelle
AU - Mirshahi, Tooraj
AU - Oetjens, Matthew
AU - Person, Thomas Nate
AU - Still, Christopher
AU - Strande, Natasha
AU - Sturm, Amy
AU - Wagner, Jen
N1 - Publisher Copyright:
© The Author(s) 2023.
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
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U2 - 10.1038/s41588-023-01417-8
DO - 10.1038/s41588-023-01417-8
M3 - Article
C2 - 37308787
AN - SCOPUS:85164287940
SN - 1061-4036
VL - 55
SP - 1138
EP - 1148
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -