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Sequence variants at CHRNB3CHRNA6 and CYP2A6 affect smoking behavior


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 × 10−8), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 × 10−69), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 × 10−12) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 × 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 dependence2,3,4. 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).

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Figure 1: Regional plots of the CPD loci.

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We thank all the participants in the genetic studies whose contributions made this work possible. This work was supported in part by the US National Institutes of Health (R01-DA017932) and the European Commission's Sixth Framework Program, Integrated Project GENADDICT (LSHM-CT-2004-005166). The ENGAGE smoking consortium was formed through a component of the Integrated Project ENGAGE, supported by the European Commission's Seventh Framework Program, grant agreement HEALTH-F4-2007- 201413. ENGAGE projects have benefited from the SIMBioMS platform28, which has greatly facilitated data exchange and annotation. Further acknowledgments are listed in the Supplementary Note online.

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Authors and Affiliations




The study was designed by and the results interpreted by T.E.T., D.F.G., F.G., J.R.G., U.T., K.S., L.P. and M.I.M. The meta-analysis was performed by D.F.G. and F.G., and D.F.G., F.G., I.S., J.M.V., P.S., N.A., T.E., S.W., C.G., R.R., M.M., I.P., R.M., J. Kettunen, Y.S.A., N.S. and J.J.H. were responsible for data analysis in each of the ENGAGE samples. Stage 3 and smoking-related disease samples were coordinated by I.H.G., H.S., S.G. and T.R. Those responsible for case and control ascertainment, recruitment and phenotypic information and project management at the study sites are: J.R.T., W.A.F., H.W., G.W.M., A.C.H., N.G.M., P.A.F.M., K.K.A., M.d.H., L.A.K., G.T.J., A.M.v.R., T.M., B.D., M.H., S.J., T.R., S.E.M., S.G., A.M.V., C.S., A.G.U., A.H., A.T., P.K., G.W., N.V., A. Dirksen, N.D., B.N., M.L.P., B.S., S.R., M.P., J. Kettunen, A.-L.H., A.P., J.L., M.I., A.S.H., T.E.T., H.O., T.T., V.D.D., V.L., M.D.G.-P., J.I.M., A. Döring, H.A., J.S.L., J.H.P., I.G., D.R., M.-R.J., V.S., M.S., T.D.S., H.-E.W., A.M., M.N., N.J.S., B.W.P., B.A.O., D.I.B., H.T., C.M.v.D., J. Kaprio, J.R.G., M.I.M., L.P., U.T. and K.S. Data submission coordination was provided by S.H.-Y., M.A. and M.K. Authors T.E.T., D.F.G. and U.T. wrote the first draft of the paper. All authors contributed to the final version of the paper.

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Correspondence to Unnur Thorsteinsdottir or Kari Stefansson.

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Authors whose affiliations are listed as deCODE genetics are employees of deCODE genetics, a biotechnology company.

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A full list of members is provided in the Supplementary Note.

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Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note (PDF 215 kb)

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Thorgeirsson, T., Gudbjartsson, D., Surakka, I. et al. Sequence variants at CHRNB3CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42, 448–453 (2010).

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