Rare coding variants in CHRNB3 associate with reduced daily cigarette smoking across ancestries

Rare coding variants that alter protein function and confer beneficial health effects can suggest potential drug targets. CHRNB3 encodes the β3 subunit of nicotinic acetylcholine receptors that bind nicotine and mediate its action in the brain. Here we report an exome-wide association study of number of cigarettes smoked per day (cig per day) in 37,897 current smokers from the Mexico City Prospective Study. We identify a deleterious missense variant in CHRNB3, p.Glu284Gly, that associates with a significant reduction in daily cigarette consumption. The missense variant is enriched in people of Indigenous Mexican ancestry but rare in other ancestries. We further identify a predicted loss-of-function variant in CHRNB3 that significantly associates with reduction in number of smoked cigarettes per day in participants of Japan Biobank. This variant is enriched in people of East Asian ancestry but is rare in other ancestries. Finally, we find that rare deleterious missense and predicted loss-of-function variants in aggregate associate with a reduction in the number of smoked cigarettes per day in individuals of European ancestry from the UK Biobank. Our results suggest that loss of function of CHRNB3 significantly associates with daily cigarette smoking, proposing β3 inhibition as a potential therapeutic strategy for nicotine addiction.

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Journal
Nature Communications
Published
2026-02-24
DOI
https://doi.org/10.1038/s41467-026-68825-2
Primary Topic
Nicotinic Acetylcholine Receptors Study
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article
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article

Rare coding variants in CHRNB3 associate with reduced daily cigarette smoking across ancestries

Marcus Herbert Jones, Tyler Joseph, Lori A. Crane, Samantha Rodríguez Zárate et al.
Nature Communications
Nicotinic Acetylcholine Receptors Study
article

Rare coding variants in CHRNB3 associate with reduced daily cigarette smoking across ancestries

Marcus Herbert Jones, Tyler Joseph, Lori A. Crane, Samantha Rodríguez Zárate, Alan R. Shuldiner, Muhammad Aqeel, Zhenhua Gu, Jason Portnoy, Mira Y. Tang, E. Jorgenson, Luca Lotta, Jingning Zhang, Adolfo A. Ferrando, Pablo Antonio Kuri-Morales, Jacqueline M. Otto, Carlo Sidore, Larizbeth A. Romero, Jody L. Hankins, Mohsin Ahmed, Sheila M. Gaynor, Jason Torres, George Hindy, Antoine Baldassari, Sarah E. Graham, Michael D. Kessler, Andrey Ziyatdinov, Amit D. Joshi, Ernst Mayerhofer, Arthur Gilly, Alison Fenney, Luanluan Sun, Jesús Alegre-Díaz, Fontanillas, John S. Overton, L Zhang, Joelle Mbatchou, Manan Mohan Goyal, Timothy A. Thornton, José Brás, Amelia Averitt, Gonçalo R. Abecasis, William Hunt Palmer, Joshua Backman, Michelle G. LeBlanc, Sunilbe Siceron, Manav Kapoor, De Tanima, Chen Wang, Vijay Kumar, Adrián Campos, Hang Du, Chuanyi Zhang, Sarah Wolf, Nan Lin, Bin Ye, Cristen J. Willer, Alexander Lopez, Amy J. Damask, Xiaodong Bai, Michael Lattari, Bovijn Jonas, Adam E. Locke, Vrushali Mahajan, Joseph L. Herman, Ricardo Schiavo, Jennifer Rico Varela, Salvador Romero Martinez, Dhruv Shidhaye, Rujin Wang, Niek Verweij, Eli Stahl, Sahar Gelfman, Roberto Tapia-Conyer, Gannie Tzoneva, Yuxin Zou, Jonathan R. Emberson, Peter Dornbos, Adam J. Mansfield, Karl Landheer, Christopher Gillies, Mudasar Sarwar, Suganthi Balasubramanian, Johannie Rivera-Picart, Lei Chen, Sean Yu, Boris Boutkov, Jonathan Marchini, Anita Pandit, Anna Alkelai, Sameer Malhotra, Anthony Marcketta, Benjamin Geraghty, Pooja Mule, Liron Ganel, William Salerno, Ariane Ayer, Frank Wendt, Ryan Smith, Kuan-Han Wu, Ashley Paynter, Prathyusha Challa, Razvan Panea, Evan K. Maxwell, Brian Hobbs, Kimberly Skead, Alexander Lachmann, John D. Overton, Alexander Gorovits, Katherine Siminovitch, Rouel Lanche, Moeen Riaz, Giovanni Coppola, Olivier Delaneau, Sean O’Keeffe, Maria Sotiropoulos Padilla, Blair Zhang, David Corrigan, Sanjay Sreeram, Maya Ghoussaini, Jaime Berumen, Gisu Eom, Ju Guan, Jonathan Ross, Christina Beechert, Lyndon Mitnaul, Michael Cantor, Valentina Zavala, George Mitra, Esteban Chen, Aaron Zhang, Juan Rodriguez-Flores, Jae Soon Sul, Krishna Pawan Punuru, Keyrun Adhikari, Nilanjana Banerjee, Anna Han, Raymond Reynoso, Samuel Hart, Suying Bao, Ayesha Rasool, Chenggu Wang, Sujit Gokhale, Lukas Habegger, Mary Haas, Nadia Rana, Joana Revez, Kristy Guevara, Alicia Hawes, Sam Choi, Olukayode Sosina, Charles Paulding, Kathie Sun, Michelle Pagan, Mona Nafde, Aris Baras, Jeffrey G. Reid, Gina Solari, Jon Silver, Rita Guerreiro, Priyanka Nakka
article en

Abstract

Rare coding variants that alter protein function and confer beneficial health effects can suggest potential drug targets. CHRNB3 encodes the β3 subunit of nicotinic acetylcholine receptors that bind nicotine and mediate its action in the brain. Here we report an exome-wide association study of number of cigarettes smoked per day (cig per day) in 37,897 current smokers from the Mexico City Prospective Study. We identify a deleterious missense variant in CHRNB3, p.Glu284Gly, that associates with a significant reduction in daily cigarette consumption. The missense variant is enriched in people of Indigenous Mexican ancestry but rare in other ancestries. We further identify a predicted loss-of-function variant in CHRNB3 that significantly associates with reduction in number of smoked cigarettes per day in participants of Japan Biobank. This variant is enriched in people of East Asian ancestry but is rare in other ancestries. Finally, we find that rare deleterious missense and predicted loss-of-function variants in aggregate associate with a reduction in the number of smoked cigarettes per day in individuals of European ancestry from the UK Biobank. Our results suggest that loss of function of CHRNB3 significantly associates with daily cigarette smoking, proposing β3 inhibition as a potential therapeutic strategy for nicotine addiction.

Nature CommunicationsVol. 17(1)
Regeneron (United States) (US), University of Oxford (GB), Universidad Nacional Autónoma de México (MX), Tecnológico de Monterrey (MX)
Good health and well-being
Openalex Percentile: Top 44%
Nicotinic Acetylcholine Receptors Study
DOIOpen Access PDFOpenAlex
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