Rare coding variants in CHRNB2 reduce the likelihood of smoking
Authors: 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 ,   GHS-REGN DiscovEHR collaboration, 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 , Williams Marc ,   Regeneron Genetics Center,   RGC Management & Leadership Team, Economides Aris , Deubler Andrew , Karalis Katia , Lotta Luca A. , Overton John D. , Reid Jeffrey G. , Siminovitch Katherine , Mitnaul Lyndon J. , Shuldiner Alan , Ferrando Adolfo ,   Sequencing & Lab Operations, Beechert Christina , Forsythe Caitlin , Brian Erin D. , Gu Zhenhua , Lattari Michael , Lopez Alexander , Sotiropoulos Maria , Pradhan Manasi , Manoochehri Kia , Schiavo Ricardo , Reynoso Raymond , Guevara Kristy , Cremona Laura M. , Wang Chenggu , Du Hang , Wolf Sarah E. ,   Clinical Informatics, Averitt Amelia , Banerjee Nilanjana , Li Dadong , Malhotra Sameer , Mower Justin , Sundaram Jay , Zhang Aaron , Yu Sean , Sarwar Mudasar , Staples Jeffrey C. ,   Genome Informatics & Data Engineering, Bai Xiaodong , Zhang Lance , O’Keeffe Sean , Bunyea Andrew , Habegger Lukas , Boutkov Boris , Eom Gisu , Hawes Alicia , Krasheninina Olga , Lanche Rouel , Mansfield Adam J. , Edelstein Evan , Gokhale Sujit , Gorovits Alexander , Maxwell Evan K. , Guan Ju , Mitra George , Clauer Janice , Nafde Mona , Mahajan Vrushali , Panea Razvan , Makkena Koteswararao , PawanPunuru Krishna , Sultan Benjamin , Sreeram Sanjay , Polanco Tommy , Rasool Ayesha , Salerno William J. , Sun Kathie ,   Analytical Genetics and Data Science, Backman Joshua , Marcketta Anthony , Ye Bin , Gurski Lauren , Lin Nan , Revez Jan , Zou Yuxin , Kosmicki Jack , Ross Jonathan , Ziyatdinov Andrey , Stahl Eli , Ghosh Akropravo , Chen Lei , Wang Rujin , Locke Adam , Sidore Carlo , Moscati Arden , Dobbyn Lee , Zhang Blair , Gillies Christopher , Kessler Michael , Suciu Maria , Thornton Timothy , Nakka Priyanka , Gaynor Sheila , Joseph Tyler , Geraghty Benjamin , Pandit Anita , Herman Joseph , Choi Sam , VandeHaar Peter , Ganel Liron , Wu Kuan-Han , Pandey Aditeya , Burch Kathy , Campos Adrian , Vrieze Scott , Vedantam Sailaja , Paulding Charles , Damask Amy ,   Therapeutic Area Genetics, Guvenek Aysegul , Hindy George , Jan Freudenberg  , Bovijn Jonas , Haas Mary , Riaz Moeen , Verweij Niek , Sosina Olukayode , Akbari Parsa , De Tanima , Tzoneva Gannie , He Jin , Alvarez Silvia , Sosina Kayode , Otto Jacqueline , Alkelai Anna , Kumar Vijay , Dombos Peter , Joshi Amit , Graham Sarah , Sun Luanluan , Baldassari Antoine , Brown Jessie , Willer Cristen J. , Gilly Arthur , Khiabanian Hossein , Hobbs Brian , Palmer Billy , Rodriguez-Flores Juan ,   Research Program Management & Strategic Initiatives, Hernandez Jaimee , LeBlanc Michelle G. , Mighty Jason , Nishtala Nirupama , Rana Nadia , Rico-Varela Jennifer ,   Strategic Partnerships & Business Operations, Schwartz Randi , Coleman Thomas , Fenney Alison , Hankins Jody , Cox Ruan , Hart Samuel , Shuldiner Alan R. , Balasubramanian Suganthi , Abecasis Gonçalo R. , Kang Hyun M. , Marchini Jonathan , Stahl Eli A. , Jorgenson Eric , Sanchez Robert , Liedtke Wolfgang , Anderson Matthew , Cantor Michael , Lederer David , Baras Aris , Coppola Giovanni 
Published: June 2023

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.