Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

Thorgeir E. Thorgeirsson, Daniel F. Gudbjartsson, Ida Surakka, Jacqueline M. Vink, Najaf Amin, Frank Geller, Patrick Sulem, Thorunn Rafnar, Tõnu Esko, Stefan Walter, Christian Gieger, Rajesh Rawal, Massimo Mangino, Inga Prokopenko, Reedik Mägi, Kaisu Keskitalo, Iris H. Gudjonsdottir, Solveig Gretarsdottir, Hreinn Stefansson, John R. ThompsonYurii S. Aulchenko, Mari Nelis, Katja K. Aben, Martin Den Heijer, Asger Dirksen, Haseem Ashraf, Nicole Soranzo, Ana M. Valdes, Claire Steves, André G. Uitterlinden, Albert Hofman, Anke Tönjes, Peter Kovacs, Jouke Jan Hottenga, Gonneke Willemsen, Nicole Vogelzangs, Angela Döring, Norbert Dahmen, Barbara Nitz, Michele L. Pergadia, Berta Saez, Veronica De Diego, Victoria Lezcano, Maria D. Garcia-Prats, Samuli Ripatti, Markus Perola, Johannes Kettunen, Anna Liisa Hartikainen, Anneli Pouta, Jaana Laitinen, Matti Isohanni, Shen Huei-Yi, Maxine Allen, Maria Krestyaninova, Alistair S. Hall, Gregory T. Jones, Andre M. Van Rij, Thomas Mueller, Benjamin Dieplinger, Meinhard Haltmayer, Steinn Jonsson, Stefan E. Matthiasson, Hogni Oskarsson, Thorarinn Tyrfingsson, Lambertus A. Kiemeney, Jose I. Mayordomo, Jes S. Lindholt, Jesper Holst Pedersen, Wilbur A. Franklin, Holly Wolf, Grant W. Montgomery, Andrew C. Heath, Nicholas G. Martin, Pamela A.F. Madden, Ina Giegling, Dan Rujescu, Marjo Riitta Järvelin, Veikko Salomaa, Michael Stumvoll, Tim D. Spector, H. Erich Wichmann, Andres Metspalu, Nilesh J. Samani, Brenda W. Penninx, Ben A. Oostra, Dorret I. Boomsma, Henning Tiemeier, Cornelia M. Van Duijn, Jaakko Kaprio, Jeffrey R. Gulcher, Mark I. McCarthy, Leena Peltonen, Unnur Thorsteinsdottir, Kari Stefansson

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Smoking is a common risk factor for many diseases1. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P 5 × 108), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 × 1069), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 × 1012) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 × 108), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).

Original languageEnglish
Pages (from-to)448-453
Number of pages6
JournalNature Genetics
Issue number5
StatePublished - May 2010


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