Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.
Thorgeirsson TE., Gudbjartsson DF., Surakka I., Vink JM., Amin N., Geller F., Sulem P., Rafnar T., Esko T., Walter S., Gieger C., Rawal R., Mangino M., Prokopenko I., Mägi R., Keskitalo K., Gudjonsdottir IH., Gretarsdottir S., Stefansson H., Thompson JR., Aulchenko YS., Nelis M., Aben KK., den Heijer M., Dirksen A., Ashraf H., Soranzo N., Valdes AM., Steves C., Uitterlinden AG., Hofman A., Tönjes A., Kovacs P., Hottenga JJ., Willemsen G., Vogelzangs N., Döring A., Dahmen N., Nitz B., Pergadia ML., Saez B., De Diego V., Lezcano V., Garcia-Prats MD., Ripatti S., Perola M., Kettunen J., Hartikainen A-L., Pouta A., Laitinen J., Isohanni M., Huei-Yi S., Allen M., Krestyaninova M., Hall AS., Jones GT., van Rij AM., Mueller T., Dieplinger B., Haltmayer M., Jonsson S., Matthiasson SE., Oskarsson H., Tyrfingsson T., Kiemeney LA., Mayordomo JI., Lindholt JS., Pedersen JH., Franklin WA., Wolf H., Montgomery GW., Heath AC., Martin NG., Madden PAF., Giegling I., Rujescu D., Järvelin M-R., Salomaa V., Stumvoll M., Spector TD., Wichmann H-E., Metspalu A., Samani NJ., Penninx BW., Oostra BA., Boomsma DI., Tiemeier H., van Duijn CM., Kaprio J., Gulcher JR., ENGAGE Consortium None., McCarthy MI., Peltonen L., Thorsteinsdottir U., Stefansson K.
Smoking is a common risk factor for many diseases. 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 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).