Academic Journal
Rare coding variants in CHRNB2 reduce the likelihood of smoking
| العنوان: | Rare coding variants in CHRNB2 reduce the likelihood of smoking |
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| المؤلفون: | Rajagopal, Veera M., Watanabe, Kyoko, Mbatchou, Joelle, Ayer, Ariane, Quon, Peter, Sharma, Deepika, Kessler, Michael D., Praveen, Kavita, Gelfman, Sahar, Parikshak, Neelroop, Otto, Jacqueline M., Bao, Suying, Chim, Shek Man, Pavlopoulos, Elias, Avbersek, Andreja, Kapoor, Manav, Chen, Esteban, Jones, Marcus B., Leblanc, Michelle, Emberson, Jonathan, Collins, Rory, Torres, Jason, Morales, Pablo Kuri, Tapia-Conyer, Roberto, Alegre, Jesus, Berumen, Jaime, Adams, Lance J., Blank, Jackie, Bodian, Dale, Boris, Derek, Buchanan, Adam, Carey, David J., Colonie, Ryan D., Davis, F. Daniel, Hartzel, Dustin N., Kelly, Melissa, Kirchner, H. Lester, Leader, Joseph B., Ledbetter, David H., Manus, J. Neil, Martin, Christa L., Metpally, Raghu P., Meyer, Michelle, Mirshahi, Tooraj, Oetjens, Matthew, Person, Thomas Nate, Still, Christopher, Strande, Natasha, Sturm, Amy, Wagner, Jen |
| المساهمون: | RCUK | Medical Research Council, Wellcome Trust |
| المصدر: | Nature Genetics ; volume 55, issue 7, page 1138-1148 ; ISSN 1061-4036 1546-1718 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41588-023-01417-8 |
| الاتاحة: | http://dx.doi.org/10.1038/s41588-023-01417-8 https://www.nature.com/articles/s41588-023-01417-8.pdf https://www.nature.com/articles/s41588-023-01417-8 |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.5668B53B |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41588-023-01417-8 |
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