Multi-ancestry genome-wide gene–smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids

Abstract

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene–smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

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Fig. 1: Study overview.
Fig. 2: Interaction of rs12740061 (LOC105378783) and current smoking status (1df).
Fig. 3: Associations observed primarily in one smoking stratum.
Fig. 4: Forest plots of select associations.

Data availability

All summary results will be made available in dbGaP (phs000930.v7.p1).

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Acknowledgements

The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Human Genome Research Institute; the National Institutes of Health; or the US Department of Health and Human Services. This project was largely supported by a grant from the US National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL118305) and by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health through the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). Additional and study-specific acknowledgments appear in the Supplementary Note.

Author information

All authors reviewed and approved the manuscript. Study concept and design: A.B.Z., A.C.M., A.C.P., A.J.O., A.R., A.R.B., A.R.W., B.I.F., B.L.H., C.A.M.K., C. Ballantyne, C. Bouchard, C.C.K., C.C.L., C.D.L., C.H., C. Langenberg, C.M.v.D., C.M.K., C.N.R., C.-T.L., C.Y., C.-Y.C., D.C.R., D.I.C., D.M.B., D.R.W., D.W.B., E.B., E.P.B., E.R.F., E.S.T., F.R.R., G.W., H.A., H.J.d.S., H. Watkins, I.G., I.J.D., I.K., J.B.J., J. Ding, J. Divers, J.D.F., J. E. Hixson, J.E.K., J.I.R., J.K., Jianjun Liu, J.M.C., J.M.S., J.-M.Y., K.C., K.K.L., K.L.M., L.A.C., Lifelines Cohort Study, L.E.W., L.J.L., M.A.I., M.A.P., M. Brown, M. Boehnke, M. Farrall, M. Fornage, M. He, M.K., M.K.E., M. Laakso, M.S., N.G.F., N.J.S., N.J.W., N.K., N.L.P., N.P., N.S., O.P., O.T.R., P.F., P.G., P.H., P.K., P.K.E.M., P.M.R., P.S., R.A.S., R.M.D., R.R., R.S.C., S.C., S.K.M., S.L.R.K., S.R., S.T.T., T.A., T.A.L., T.B.H., T.F., T.K.R., T. Lehtimäki, T.N.K., T.R., T.W., T.Y.W., U.d.F., V.G., W.B.W., W.P.K., X.G., Y.K., Y. Liu, Y.W., Y.X.W., and Y.Y.T. Phenotype data acquisition and/or quality control: A.B.Z., A.C., A.C.P., A.D.M., A.G., A.J.O., A.K., A. Metspalu, A.P., A.P.R., A.R.B., A.R.V.R.H., A.R.W., A.W.M., B.E.C., B.G., B.I.F., B.L.H., B.M.P., B.O.T., B. Penninx, C.A.M.K., C. Ballantyne, C. Bouchard, C.D.L., C.E.L., C. Gieger, C.H., C.J., C. Langenberg, C. Li, C.M.K., C.M.v.D., C.N.R., C.O.S., C.P.N., C.Y., D.C.R., D.H., D.M.B., D.R.J., D.R.W., D.W.B., E.E., E.P.B., E.S.T., F.R., F.R.R., F.-C.H., G.J.P., G.R.B., G.W., H.G., H.J.d.S., H.J.G., H.M.S., H. Tiemeier, H. Wang, I.J.D., I.K., I.-T.L., J.A.S., J.B.J., J. Ding, J. Divers, J.D.F., J.E.K., J.H.Z., Jian’an Luan, Jingjing Liang, J.M.C., J.M.S., J.-M.J.J., J.-M.Y., J.-S.W., K.C., K.K.L., K. Leander, K. Liu, K. Schwander, K.-H.L., L.A.C., Lifelines Cohort Study, L.F.B., L.J.B., L.M., L.M.R., L.R.Y., M. Alver, M. Amini, M.A.P., M. Brown, M. Boissel, M.C., M.F.F., M. He, M. Hirata, M.K., M.K.E., M.K.W., M.N., M.P.C., M.S., M.W., N.F., N.G.F., N.J.S., N.J.W., N.L.P., N.P., N.S., N.Y.Q.T., O.H.F., O.P., O.T.R., P.A.P., P.H., P.J.S., P.K., P.K.E.M., P.M.R., P.S., P.W.F., R.A.S., R.M., R.M.D., R.R., R.S.C., S.E.H., S.L.R.K., S.S., S.S.R., S.T.T., T.A.L., T.E., T.F., T.K., T.K.R., T. Lehtimäki, T.M., T.N.K., T.R., T.S., T.W., T.-D.W., U.d.F., Understanding Society Scientific Group, W.B.W., W.P.K., Y.C.T., Y. Liu, and Y. Lu. Genotype data acquisition and/or quality control: A.B.Z., A.C.P., A.G., A.G.U., A.L., A. Metspalu, A.R.B., A.R.V.R.H., A.T.K., A.V.S., B.E.C., B.G., B.I.F., B.L.H., B.M.P., B.O.T., B. Prins, C. Bouchard, C.C.K., C.C.L., C. Gao, C.K., C. Langenberg, C. Li, C.M.K., C.N.R., C.P.N., C.-K.H., C.-T.L., D.C.R., D.E.A., D.I.C., D.M.B., D.O.M.-K., E.B., E.B.W., E.E., E.L., E.P.B., E.R.F., E.S.T., E.Z., F.G., F.P.H., F.R., F.R.R., F.-C.H., H.G., H. Wang, I.J.D., I.K., I.M.N., J.A.S., J. E. Hixson, J. E. Huffman, J.E.K., J.F.C., J.H.Z., J.I.R., Jian’an Luan, Jingjing Liang, Jianjun Liu, Jingmin Liu, J.M.C., J.M.S., K.C., K.D.T., K.K.L., K. Leander, K. Schwander, K. Strauch, L.A.C., Lifelines Cohort Study, L.M., L.M.R., L.R.Y., Lan Wang, L.-P.L., M. Alver, M. Amini, M.A.N., M.A.P., M. Boissel, M.C., M. Fornage, M.F.F., M.K., M.K.E., M.P., M.P.C., N.A., N.D.P., N.J.S., N.J.W., N.K., N.L.P., N.S., O.P., P.B.M., P.H., P.J.V.M., P.K.E.M., P.W.F., R.A.S., R.D., R.J.F.L., R.M., R.N.E., S.E.H., S.H., S.K.M., S.L.R.K., S.S.R., S.T.T., T.E., T.K.R., T. Lehtimäki, T.N.K., T.R., U.d.F., Understanding Society Scientific Group, W. Zhao, X.D., X.S., X.Z., Y.F., Y.H., Y. Liu, Y. Momozawa, Y.Y.T., Y.-D.I.C., and Z.A. Data analysis and interpretation: A.B.Z., A.C.M., A.C.P., A.G., A. Mahajan, A.P.M., A.P.R., A.R., A.R.B., A.R.V.R.H., A.S., A.U.J., A.V.S., B.I.F., B.K., B.M.P., B.O.T., B. Prins, C.A.W., C. Bouchard, C.D.L., C. Gao, C. Gieger, C. Li, C.N.R., C.P.N., C.-T.L., C.-Y.C., D.C.R., D.H., D.I.C., D.M.B., D.O.M.-K., D.V., E.B.W., E.E., E.L., E.R.F., E.S.T., F.G., F.P.H., F.T., F.-C.H., G.C., G.W., H.G., H.S., I.G., I.M.N., I.N., J.A.S., J.B.J., J. Divers, J. E. Hixson, J. E. Huffman, J.F.C., J.H.Z., Jian’an Luan, Jingmin Liu, J.S.F., J.Y., J.Z., K. Leander, K.R., L.A.C., Lifelines Cohort Study, L.F.B., L.M.R., L.R.Y., Lan Wang, Lihua Wang, L.-P.L., M. Amini, M.A.N., M.A.R., M.A.S., M. Fornage, M. Farrall, M.F.F., M.K., M.K.E., M.P., M.R., M.R.B., M.S., N.D.P., N.F., N.J.S., N.M., P.A.P., P.B.M., P.H., P.J.V.M., P.S.V., R.D., R.J.F.L., R.N., R.N.E., R.S.C., S.A.G., S.B.K., S.E.H., S.H., S.K.M., S.L., S.L.R.K., S.M.T., T.K.R., T. Louie, T.M.B., T.N.K., T.R., T.S., T.V.V., T.W.W., T.Y.W., W.B.W., W. Zhao, X.C., X.D., X.G., X.S., Y.H., Y.J., Y.K., Y. Lu, and Y.X.W. Look-ups: A.E.J., A. Mahajan, A.P.M., A.R.B., COGENT-Kidney Consortium, D.I.C., K.Y., M.G., N.F., and T.W.W. These authors constitute the writing group: A.R.B., Y.J.S., M.R.B., T.W.W., A.T.K., I.N., K.S., X.Z., L.J.B., W.J.G., K.R., P.B.M., A.C.M., D.C.R., C.N.R., and L.A.C.

Correspondence to Amy R. Bentley or Charles N. Rotimi or L. Adrienne Cupples.

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Competing interests

The authors declare no competing interests except for the following. O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health). J.B.J. serves as a consultant for Mundipharma Co., is a patent holder with Biocompatibles UK, Ltd (“Treatment of Eye Diseases using Encapsulated Cells Encoding and Secreting Neuroprotective Factor and/or Anti-angiogenic Factor”; patent number 20,120,263,794), and has a patent application with the University of Heidelberg (“Agents for Use in the Therapeutic or Prophylactic Treatment of Myopia or Hyperopia”; Europäische Patentanmeldung 15000771.4). The participation of M.A.N. is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health; as a possible conflict of interest, M.A.N. also consults for Illumina, the Michael J. Fox Foundation, and University of California Healthcare, among others. N.P. has received financial support from several pharmaceutical companies that manufacture either blood pressure–lowering or lipid-lowering agents, or both, and consultancy fees. P.S. has received research awards from Pfizer. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. L.J.B. is listed as an inventor on issued US patent 8,080,371 (“Markers for Addiction”), covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction.

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    • , N. Verweij
    •  & Pim van der Harst

    Current Cardiology Reports (2019)

  • A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

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    Human Molecular Genetics (2019)