Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

Thorgeirsson, T.E.; Gudbjartsson, D.F.; Surakka, I.; Vink, J.M.; Amin, N.; Geller, F.; ... ; ENGAGE Consortium (2010)

Article / Letter to editor

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).

• genome-wide association nicotinic acetylcholine-receptors lung-cancer susceptibility locus molecular-genetics heavy smoking adult twins dependence genes snps

• All authors: Thorgeirsson, T.E.; Gudbjartsson, D.F.; Surakka, I.; Vink, J.M.; Amin, N.; Geller, F.; Sulem, P.; Rafnar, T.; Esko, T.; Walter, S.; Gieger, C.; Rawal, R.; Mangino, M.; Prokopenko, I.; Magi, R.; Keskitalo, K.; Gudjonsdottir, I.H.; Gretarsdottir, S.; Stefansson, H.; Thompson, J.R.; Aulchenko, Y.S.; Nelis, M.; Aben, K.K.; Heijer, M. den; Dirksen, A.; Ashraf, H.; Soranzo, N.; Valdes, A.M.; Steves, C.; Uitterlinden, A.G.; Hofman, A.; Tonjes, A.; Kovacs, P.; Hottenga, J.J.; Willemsen, G.; Vogelzangs, N.; Doring, A.; Dahmen, N.; Nitz, B.; Pergadia, M.L.; Saez, B.; Diego, V. de; Lezcano, V.; Garcia-Prats, M.D.; Ripatti, S.; Perola, M.; Kettunen, J.; Hartikainen, A.L.; Pouta, A.; Laitinen, J.; Isohanni, M.; Huei-Yi, S.; Allen, M.; Krestyaninova, M.; Hall, A.S.; Jones, G.T.; Rij, A.M. van; Mueller, T.; Dieplinger, B.; Haltmayer, M.; Jonsson, S.; Matthiasson, S.E.; Oskarsson, H.; Tyrfingsson, T.; Kiemeney, L.A.; Mayordomo, J.I.; Lindholt, J.S.; Pedersen, J.H.; Franklin, W.A.; Wolf, H.; Montgomery, G.W.; Heath, A.C.; Martin, N.G.; Madden, P.A.F.; Giegling, I.; Rujescu, D.; Jarvelin, M.R.; Salomaa, V.; Stumvoll, M.; Spector, T.D.; Wichmann, H.E.; Metspalu, A.; Samani, N.J.; Penninx, B.W.; Oostra, B.A.; Boomsma, D.I.; Tiemeier, H.; Duijn, C.M. van; Kaprio, J.; Gulcher, J.R.; McCarthy, M.I.; Peltonen, L.; Thorsteinsdottir, U.; Stefansson, K.; ENGAGE Consortium
• Date: 2010-05-31
• Journal: Nature Genetics
• Volume: 42
• Issue: 5
• Pages: 448
• DOI: doi:10.1038/ng.573