Rare coding variants in CHRNB2 reduce the likelihood of smoking

作者：Veera M. Rajagopal, Kyoko Watanabe, Joelle Mbatchou, Ariane Ayer, Peter Quon, Deepika Sharma, Michael D. Kessler, Kavita Praveen, Sahar Gelfman, Neelroop Parikshak, Jacqueline M. Otto, Suying Bao, Shek Man Chim, Elias Pavlopoulos, Andreja Avberšek, Manav Kapoor, Esteban Chen, Marcus B. Jones, Michelle G. LeBlanc, Jonathan Emberson, Rory Collins, Jason Torres, Pablo Kuri Morales, Roberto Tapia‐Conyer, Jesús Alegre-Díaz, Jaime Berúmen, Lance J. Adams, Jackie Blank, Dale L. Bodian, Derek Boris, Adam H. Buchanan, David J. Carey, Ryan Colonie, F. Daniel Davis, Dustin N. Hartzel, Melissa Kelly, H. Lester Kirchner, Joseph B. Leader, David H. Ledbetter, J. Neil Manus, Christa Lese Martin, Raghu Metpally, Michelle N. Meyer, Tooraj Mirshahi, Matthew T. Oetjens, Thomas N. Person, Christopher D. Still, Natasha T. Strande, Amy C. Sturm, Jen Wagner, Marc S. Williams, RGC Management & Leadership Team, Aris N. Economides, Andrew Deubler, Katia Karalis, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Katherine Siminovitch, Lyndon J. Mitnaul, Alan R. Shuldiner, Adolfo A. Ferrando, Sequencing & Lab Operations, Christina Beechert, Caitlin Forsythe, Erin D. Brian, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiropoulos, Manasi Pradhan, Kia Manoochehri, Ricardo Schiavo, Raymond Reynoso, Kristy Guevara, Laura M. Cremona, Chenggu Wang, Hang Du, Sarah E. Wolf, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Justin Mower, Jay Sundaram, Aaron Zhang, Sean Yu, Mudasar Sarwar, Jeffrey Staples, Genome Informatics & Data Engineering, Xiaodong Bai, Lance Zhang, Sean O’Keeffe, Andrew Bunyea, Lukas Habegger, Boris Boutkov, Gisu Eom, Alicia Hawes, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan Edelstein, Sujit Gokhale, Alexander Gorovits, Evan K. Maxwell, Ju Guan, George Mitra, Janice Clauer, Mona Nafde, Vrushali Mahajan, Razvan Panea, Koteswararao Makkena, Krishna PawanPunuru, Benjamin Sultan, Sanjay Sreeram, Tommy Polanco, Ayesha Rasool, William Salerno, Kathie Sun, Analytical Genetics and Data Science, Joshua Backman, Anthony Marcketta, Bin Ye, Lauren Gurski, Nan Lin, Jan Revez, Yuxin Zou, Jack A. Kosmicki, Jonathan Ross, Andrey Ziyatdinov, Eli A. Stahl, Akropravo Ghosh, Lei Chen, Rujin Wang, Adam E. Locke, Carlo Sidore, Arden Moscati, Lee Dobbyn, Blair Zhang, Christopher E. Gillies, Michael D. Kessler, Maria Suciu, Timothy A. Thornton, Priyanka Nakka, Sheila M. Gaynor, Tyler Joseph, Benjamin Geraghty, Anita Pandit, Joseph Herman, Sam Choi, Peter VandeHaar, Liron Ganel, Kuan-Han H. Wu, Aditeya Pandey, Kathy Burch, Adrián I. Campos, Scott Vrieze, Sailaja Vedantam, Charles Paulding, Amy Damask, Therapeutic Area Genetics, Ayşegül Güvenek, George Hindy, Jan Freudenberg, Jonas Bovijn, Mary E. Haas, Moeen Riaz, Niek Verweij, Olukayode Sosina, Parsa Akbari, Tanima De, Gannie Tzoneva, Jin He, Silvia Álvarez, Kayode Sosina, Jacqueline M. Otto, Anna Alkelai, Vijay Kumar, Peter Dombos, Amit D. Joshi, Sarah E. Graham, Luanluan Sun, Antoine Baldassari, Jessie Brown, Cristen J. Willer, Arthur Gilly, Hossein Khiabanian, Brian D. Hobbs, Billy Palmer, Juan L. Rodríguez-Flores, Jaimee Hernandez, Michelle G. LeBlanc, Jason Mighty, Nirupama Nishtala, Nadia Rana, Jennifer Rico‐Varela, Strategic Partnerships & Business Operations, Randi Schwartz, Thomas R. Coleman, Alison Fenney, Jody Hankins, Ruan Cox, Samuel F. M. Hart, Alan R. Shuldiner, Suganthi Balasubramanian, Gonçalo R. Abecasis, Hyun Min Kang, Jonathan Marchini, Eli A. Stahl, Eric Jorgenson, Robert J. Sanchez, Wolfgang Liedtke, Matthew P. Anderson, Michael Cantor, David J. Lederer, Aris Baras, Giovanni Coppola · 发表于：Nature Genetics · 年份：2023 · DOI：10.1038/s41588-023-01417-8 · 被引用次数：17 · 研究领域：RNA modifications and cancer、RNA Research and Splicing、RNA and protein synthesis mechanisms

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.