Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

TE Thorgeirsson, DF Gudbjartsson, I Surakka, JM Vink, Najaf Amin, F Geller, P Sulem, T Rafnar, T Esko, Stefan Walter, C Gieger, R Rawal, M Mangino, I Prokopenko, R Magi, K Keskitalo, IH Gudjonsdottir, S Gretarsdottir, H Stefansson, JR ThompsonYS Aulchenko, M Nelis, KK Aben, Mariska Heijer, A Dirksen, H Ashraf, N Soranzo, AM Valdes, C Steves, André Uitterlinden, Bert Hofman, A Tonjes, P Kovacs, JJ (Jouke Jan) Hottenga, G Willemsen, N Vogelzangs, A Doring, N Dahmen, B Nitz, ML Pergadia, B Saez, V De Diego, V Lezcano, MD Garcia-Prats, S Ripatti, M Perola, J Kettunen, AL Hartikainen, A Pouta, J Laitinen, M Isohanni, S Huei-Yi, M Allen, M Krestyaninova, AS Hall, GT Jones, AM van Rij, T Mueller, B Dieplinger, M Haltmayer, S Jonsson, SE Matthiasson, H Oskarsson, T Tyrfingsson, LA Kiemeney, JI Mayordomo, JS Lindholt, JH Pedersen, WA Franklin, H Wolf, GW Montgomery, AC Heath, NG Martin, PAF Madden, I Giegling, D Rujescu, MR Jarvelin, V Salomaa, M Stumvoll, TD Spector, HE Wichmann, A Metspalu, NJ Samani, BW Penninx, Ben Oostra, DI Boomsma, Henning Tiemeier, Cornelia Duijn, J Kaprio, JR Gulcher, MI McCarthy, L Peltonen, U Thorsteinsdottir, K Stefansson

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Smoking is a common risk factor for many diseases(1). 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 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), 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 dependence2-4. 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 languageUndefined/Unknown
Pages (from-to)448-U135
JournalNature Genetics
Issue number5
Publication statusPublished - 2010

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