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Genome-wide meta-analyses identify multiple loci associated with smoking behavior

Abstract

Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10−73). Two 10q25 SNPs (rs1329650[G], β = 0.367, s.e. = 0.059, P = 5.7 × 10−10; and rs1028936[A], β = 0.446, s.e. = 0.074, P = 1.3 × 10−9) and one 9q13 SNP in EGLN2 (rs3733829[G], β = 0.333, s.e. = 0.058, P = 1.0 × 10−8) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04–1.08, P = 1.8 × 10−8). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08–1.18, P = 3.6 × 10−8) was significantly associated with smoking cessation.

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Figure 1: Genome-wide association results for the TAG Consortium.
Figure 2: Forest and regional plots of significant associations for CPD from meta-analyses of the TAG, Ox-GSK and ENGAGE consortia.
Figure 3: Forest and regional plots of significant associations for smoking behavior.

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Acknowledgements

This work was funded by the University of North Carolina Lineberger Comprehensive Cancer Center University Cancer Research Fund Award and by US National Cancer Institute K07 CA118412 to H.F. Statistical analyses were carried out on the Genetic Cluster Computer (see URLs), which is supported by the Netherlands Scientific Organization (NWO 480-05-003). Acknowledgments for studies included in TAG are listed in the Supplementary Note.

Author information

Authors and Affiliations

Consortia

Contributions

TAG: study conception, design, management: H.F., P.F.S., Y.K., J. Dackor; TAG Statistical Working Group: D.-Y.L., P.K., J.P.A.I., D.P., H.F., Y.K., J. Dackor, S.P.F., N.F., E.H.L., J.D.M., J.M.V., D.I.B., D.L., B.M.E., E.L.T., B. McKnight, P.F.S., D. Absher; TAG Phenotype Working Group: C. Lerman, J.K., H.H.M., L.M.T., J.A.-M., E.H.L., J.E.R., M.D.L., J.M.V., H.F., Y.K., J. Dackor, S.P.F., P.F.S., E.L.T.; data analysis: Y.K., D.M.A., F.G., E.H.L., J.D.M., J.M.V., A.U.J., L. Bernardinelli, S.R.P., S.-J.H., B.M.E., C. Ladenvall, J.R.B.P., T.T., E.L.T., J.C.B., G.L., S.W.; TAG Manuscript Writing Group: H.F., Y.K., J. Dackor, P.F.S., C. Lerman, M.D.L., J.K., J.A.-M., P.K. All authors reviewed and approved the final version of the manuscript. The corresponding authors had access to the full data set of summary results contributed by each study.

ARIC: study conception, design, management: E.B.; phenotype collection, data management: N.F.; sample processing and genotyping: N.F.; data analysis: Y.K., N.F.

Atherosclerosis Thrombosis and Vascular Biology Italian Study Group: study conception, design, management: L. Bernardinelli, P.M.M., P.A.M., D. Ardissino; phenotype collection, data management: F.M., L. Bernandinelli; data analysis: L. Bernandinelli.

ADVANCE: study conception, design, management: S.P.F., D. Absher, T.Q., C.I., T.L.A., J.W.K.; phenotype collection, data management: S.P.F., T.Q., C.I., T.L.A., J.W.K.; sample processing and genotyping: D. Absher, T.Q.; data analysis: S.P.F., D. Absher, T.L.A., J.W.K.

Baltimore Longitudinal Study of Aging: study conception, design, management: L. Ferrucci; phenotype collection, data management: L. Ferrucci; data analysis: T.T.

CHS: study conception, design, management: B.M.P., J.C.B., C.D.F.; phenotype collection, data management: B.M.P.; sample processing and genotyping: T.H., K.D.T.; data analysis: B.M.P., E.L.T., J.C.B., B. McKnight.

DGI: study conception, design, management: L.G.; phenotype collection, data management: P.A.; data analysis: P.A., C. Ladenvall.

FUSION: study conception, design, management: K.L.M., M.B.; phenotype collection, data management: H.M.S., J.T.; data analysis: H.M.S., A.U.J.

Framingham Heart Study: study conception, design, management: R.S.V., E.J.B., D.L.; phenotype collection, data management: S.R.P., R.S.V., S.-J.H., E.J.B., D.L.; data analysis: S.R.P., S.-J.H.

GAIN: study conception, design, management: D.F.L., P.V.G.; phenotype collection, data management: A.R.S., D.F.L., J. Duan, J.S., P.V.G.; sample processing and genotyping: J. Duan, P.V.G.; data analysis: A.R.S., D.F.L., J. Duan, J.S., P.V.G.

IARC/ARCAGE/Central European GWAS: phenotype collection, data management: D.Z., N.S.-D., J.L., P.R., E.F., D.M., V.B., L. Foretova, V.J., S. Benhamou, P.L., I.H., L.R., K.K., A.A., X.C., T.V.M., L. Barzan, C.C., R.L., D.I. Conway, A.Z., C.M.H., P.B.; sample processing and genotyping: J.D.M., M.L., P.B.; data analysis: E.H.L., J.D.M.

InCHIANTI: study conception, design, management: T.M.F., J.M.G., S. Bandinelli; phenotype collection, data management: Y.M.; data analysis: J.R.B.P.

MIGEN: study conception, design, management: R.E., V.S., O.M., C.J.O., D. Altshuler; phenotype collection, data management: G.L., S.M.S., R.E., V.S., B.F.V., O.M., S.K., C.J.O.; sample processing and genotyping: S.K., D. Altshuler; data analysis: G.L., B.F.V., D. Altshuler

NESDA: study conception, design, management: B.W.P., J.H.S.; phenotype collection, data management: B.W.P., J.H.S., N.V.; sample processing and genotyping: B.W.P., J.H.S.; data analysis: N.V.

NTR: study conception, design, management: D.I.B., G.W., E.J.C.d.G.; phenotype collection, data management: D.I.B., G.W., E.J.C.d.G., J.M.V.; sample processing and genotyping: D.I.B., G.W., E.J.C.d.G.; data analysis: J.M.V.

NHS: phenotype collection, data management: S.E.H., D.J.H., P.K., F.G.; sample processing and genotyping: S.J.C., S.E.H., D.J.H., P.K.; data analysis: S.J.C., F.G., P.K.

Rotterdam: study conception, design, management: A.H.; phenotype collection, data management: H.T., A.G.U.; sample processing and genotyping: H.T., A.G.U.; data analysis: H.T., A.G.U., S.W., C.M.v.D.

WGHS: study conception, design, management: B.M.E., G.P., D.I. Chasman, P.M.R.; phenotype collection, data management: B.M.E., G.P., D.I. Chasman, P.M.R.; sample processing and genotyping: G.P., D.I. Chasman; data analysis: B.M.E., G.P., D.I. Chasman.

Corresponding authors

Correspondence to Helena Furberg or Patrick F Sullivan.

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The author declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–5, Supplementary Figures 1 and 2 and Supplementary Note (PDF 655 kb)

Supplementary Table 6

Association testing for CPD on chromosome 15, conditional on rs1051730 (XLS 46 kb)

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The Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 42, 441–447 (2010). https://doi.org/10.1038/ng.571

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