Rare coding variants in CHRNB3 associate with reduced daily cigarette smoking across ancestries
Por:
Ziyatdinov A., Joseph T., Ayer A., Ahmed M., Mbatchou J., Zou Y., Averitt A.J., Banerjee N., Cantor M., Torres J.M., Chen E., Varela J.R., Siceron S., Pagan M., Rivera-Picart J., Solari G., Perez-Beals A., Smith R., Hart S., Han A., Hankins J., Schwartz R., Paynter A., Romero L., Hernandez J., Rico-Varela J., Rana N., LeBlanc M.G., Herman J., Malhotra S., Paulding C., Lin N., Damask A., Choi S., Chen L., Sul J.S., Zavala V., Skead K., Revez J., Khiabanian H., Brown J., Alvarez S., Bras J., Otto J., Kumar V., Gelfman S., Rajagopal V., Alkelai A., Jallow M.W., Tzoneva G., Kapoor M., Riaz M., Rodriguez-Flores J., Dornbos P., Gilly A., Sosina O., Sun L., De T., Bovijn J., Hindy G., Verweij N., Haas M., Castineira E.P., Mayerhofer E., Graham S., Baldassari A., Joshi A., Guerreiro R., Palmer W., Silver J., Hobbs B., Lachmann A., Adhikari K., Shidhaye D., Corrigan D., Zhang A., Yu S., Zhang C., Sun K., Bao S., Balasubramanian S., Wendt F., Tang M., Watanabe K., Zhang J., Zhang B., Ye B., Wu K.H., Wang R., Vedantam S., Thornton T., Stahl E., Sidore C., Ross J., Pandit A., Moscati A., Marcketta A., Delaneau O., Landheer K., Nakka P., Locke A., Kosmicki J., Kessler M., Jorgenson E., Gurski L., Gillies C., Martinez S.R., Ghosh A., Geraghty B., Gaynor S., Ganel L., Campos A., Burch K., Backman J., Mansfield A.J., Zarate S., Krasheninina O., Hawes A., Habegger L., Guan J., Gorovits A., Boutkov B., Maxwell E.K., Rasool A., Edelstein E., Panea R., O’Keeffe S., Zhang L., Bai X., Aqeel M., Sarwar M., Mule P., Sultan B., Gokhale S., Punuru K.P., Eom G., Vasireddy S.L., Mahajan V., Lanche R., Sreeram S., Mitra G., Goyal M., Wolf S.E., Wang C., Padilla M.S., Schiavo R., Reynoso R., Pradhan M., Challa P., Manoochehri K., Lopez A., Lattari M., Guevara K., Gu Z., Forsythe C., Du H., Kalyuskin E., Cremona L.M., Fuller E., Beechert C., Crane L., Willer C.J., Salerno W., Nafde M., Ghoussaini M., Ferreira M.A.R., Fenney A., Mitnaul L., Jones M.B., Portnoy J., Siminovitch K., Shuldiner A., Reid J.G., Overton J.D., Lotta L.A., Deubler A., Ferrando A., Jones M., Overton J., Harari O., Lotta L., Abecasis G., Baras A., Berumen J., Kuri-Morales P., Alegre-Díaz J., Tapia-Conyer R., Collins R., Emberson J.R., Marchini J., Coppola G.
Publicada:
1 ene 2026
Resumen:
© The Author(s) 2026.Rare coding variants that alter protein function and confer beneficial health effects can suggest potential drug targets. CHRNB3 encodes the ß3 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 ß3 inhibition as a potential therapeutic strategy for nicotine addiction.
Filiaciones:
Regeneron Genetics Center, Tarrytown, NY, USA
Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA
Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
Tecnologico de Monterrey, Monterrey, Mexico
Green Submitted, gold
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