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Meta-analysis and imputation refines the association of 15q25 with smoking quantity


Smoking is a leading global cause of disease and mortality1. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 × 10−19) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

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Figure 1: Plot showing the significance of association of all SNPs in the genome-wide smoking quantity meta-analysis.
Figure 2: Chromosome 15q25 signal plots.

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GlaxoSmithKline (GSK), a pharmaceuticals company that is interested in developing new cessation therapies for smoking, funded a postdoctoral fellowship for J.Z.L. at Oxford University. GSK also funded the collection, characterization, and, in some cases, the genotyping and genotype data preparation for several of the cohorts used in this study. A. Roses and P. Matthews played crucial roles in establishing and funding the Medical Genetics activities at GSK. Acknowledgments that are specific to individual cohorts are given in the Supplementary Note.

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Authors and Affiliations




J.Z.L. carried out most of the analysis for this study. J.M. and C.F. conceived and directed this study and wrote the manuscript. F.T., D.M.W. and V.M. were involved in study design and helped to coordinate the inclusion of many of the GSK cohorts. S.G.P., P. Muglia, L.M., W.B., C.W.K., X.Y., G.W., P.V., M. Preisig, N.J.W., J.H.Z., R.J.F.L., I.B., K.-T.K., S.G., P. Barter, R. Mahley, A.K., R. McPherson, J.B.V., J. Strauss, J.L.K., A. Farmer, P. McGuffin, R.D., K.M., P. Bakke, A.G., S.L., M.I., T.B., S.H., H.-E.W., R.R., N.D., C.L., O.P., L.Z., J.H., S.C., J.K., J.C.C., M.S.B., J.M.D., A.D.P., K.M.K.. L.S., J.M.L., R. Waksman, S. Epstein, J.F.W., S.H.W., H.C., V.V., M.P.R., M.L., L.Q., R. Wilensky, W.M., H.H.H., D.J.R., A. Franke, M.W., A.S., M.U., A. Terracciano, X.X., F.B., P.S., D.S., D.St.C., D.R., G.R.A., H.J.G., A. Teumer, H.V., A.P., U.J., I.R., C.H., A.F.W., I.K., B.J.W., J.R.T., A.J.B., A.S.H., N.J.S., C.A.A., T.A., C.G.M., M. Parkes, J. Satsangi, M.C., P.B.M., M.F., A.D., J.W., W.T., S. Eyre, A.B. and W.T.C.C.C. prepared and shared data sets and, in some cases, cohort-specific results from their own primary analysis.

Corresponding authors

Correspondence to Clyde Francks or Jonathan Marchini.

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Competing interests

F.T., C.F., D.M.W., V.M., P.M., S.G.P. and C.W.K either are or were full-time employees of the company GlaxoSmithKline (GSK). GSK also funded several aspects of the study as detailed in the ACKNOWLEDGMENTS section.

Additional information

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

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Supplementary Figure 1–4, Supplementary Tables 1–3 and Supplementary Note (PDF 1744 kb)

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Liu, J., Tozzi, F., Waterworth, D. et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 42, 436–440 (2010).

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