Article | Published:

Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Nature Genetics volume 48, pages 11621170 (2016) | Download Citation

Abstract

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure–associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein–protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure–associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

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Acknowledgements

We thank the two anonymous reviewers and editors for their helpful comments. Study-specific funding sources and acknowledgments are reported in the Supplementary Note.

Author information

Author notes

    • Chunyu Liu
    • , Aldi T Kraja
    • , Jennifer A Smith
    • , Jennifer A Brody
    •  & Nora Franceschini

    These authors contributed equally to this work.

    • Georg B Ehret
    • , Christopher Newton-Cheh
    • , Daniel Levy
    •  & Daniel I Chasman

    These authors jointly directed this work.

Affiliations

  1. Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.

    • Chunyu Liu
    • , Audrey Y Chu
    • , Martin G Larson
    • , Shih-Jen Hwang
    • , Tianxiao Huan
    • , Ramachandran S Vasan
    • , Christopher J O'Donnell
    •  & Daniel Levy
  2. Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.

    • Chunyu Liu
    •  & Martin G Larson
  3. Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • Chunyu Liu
    • , Audrey Y Chu
    • , Shih-Jen Hwang
    • , Tianxiao Huan
    •  & Daniel Levy
  4. Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Aldi T Kraja
    • , E Warwick Daw
    •  & Ingrid B Borecki
  5. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

    • Jennifer A Smith
    • , Wei Zhao
    •  & Sharon L R Kardia
  6. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Jennifer A Brody
    • , Joshua C Bis
    •  & Bruce M Psaty
  7. Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Nora Franceschini
  8. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth Rice
  9. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston Texas, USA.

    • Alanna C Morrison
    • , Megan L Grove
    •  & Eric Boerwinkle
  10. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Yingchang Lu
    • , Erwin P Bottinger
    • , Omri Gottesman
    •  & Ruth J F Loos
  11. DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.

    • Stefan Weiss
    • , Marcus Dörr
    • , Stephan B Felix
    • , Rainer Rettig
    • , Henry Völzke
    •  & Uwe Völker
  12. Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.

    • Stefan Weiss
    •  & Uwe Völker
  13. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.

    • Xiuqing Guo
    • , Yii-Der Ida Chen
    • , Jie Yao
    • , Kent D Taylor
    • , Eric Kim
    •  & Jerome I Rotter
  14. Division of General Medicine, Columbia University Medical Center, New York, New York, USA.

    • Walter Palmas
  15. George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

    • Lisa W Martin
  16. Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Praveen Surendran
  17. Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.

    • Fotios Drenos
  18. MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.

    • Fotios Drenos
  19. Department of Biostatistics, University of Liverpool, Liverpool, UK.

    • James P Cook
  20. Department of Health Sciences, University of Leicester, Leicester, UK.

    • James P Cook
  21. Joseph J. Zilber School of Public Health, University of Wisconsin–Milwaukee, Milwaukee, Wisconsin, USA.

    • Paul L Auer
  22. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Audrey Y Chu
    • , Franco Giulianini
    • , Paul M Ridker
    •  & Daniel I Chasman
  23. Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Ayush Giri
    • , Krystal S Tsosie
    • , Digna R Velez Edwards
    •  & Todd L Edwards
  24. Icelandic Heart Association, Kopavogur, Iceland.

    • Johanna Jakobsdottir
    • , Albert V Smith
    •  & Vilmundur Gudnason
  25. Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Li-An Lin
    •  & Myriam Fornage
  26. Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Jeanette M Stafford
  27. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.

    • Najaf Amin
    •  & Cornelia M van Duijn
  28. Department of Data Science, School of Population Health, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Hao Mei
  29. Bill and Melinda Gates Foundation, Seattle, Washington, USA.

    • Arend Voorman
  30. Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.

    • Martin G Larson
  31. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Albert V Smith
    •  & Vilmundur Gudnason
  32. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Han Chen
  33. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Gulum Kosova
    • , Sekar Kathiresan
    •  & Christopher Newton-Cheh
  34. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.

    • Gulum Kosova
    • , Sekar Kathiresan
    •  & Christopher Newton-Cheh
  35. Division of Cardiology, Department of Medicine and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Nathan O Stitziel
  36. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

    • Nilesh Samani
  37. NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • Nilesh Samani
  38. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

    • Heribert Schunkert
  39. DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.

    • Heribert Schunkert
  40. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

    • Panos Deloukas
  41. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Panos Deloukas
  42. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Man Li
  43. Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated with the University of Lübeck, Lübeck, Germany).

    • Christian Fuchsberger
    •  & Cristian Pattaro
  44. Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.

    • Mathias Gorski
  45. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Charles Kooperberg
  46. Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • George J Papanicolaou
    •  & Jacques E Rossouw
  47. Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, USA.

    • Jessica D Faul
    •  & David R Weir
  48. Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA.

    • Claude Bouchard
  49. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Leslie J Raffel
  50. Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.

    • André G Uitterlinden
    •  & Oscar H Franco
  51. Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.

    • André G Uitterlinden
  52. Department of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
  53. Cardiology Section, Department of Medicine, Boston Veterans Administration Healthcare, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  54. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  55. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  56. Northwestern University School of Medicine, Chicago, Illinois, USA.

    • Kiang Liu
  57. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Santhi Ganesh
  58. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • Santhi Ganesh
  59. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Elias Salfati
    • , Aravinda Chakravarti
    •  & Georg B Ehret
  60. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Tamara B Harris
  61. Neuroepidemiology Section, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Lenore J Launer
  62. Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.

    • Marcus Dörr
    •  & Stephan B Felix
  63. Institute of Physiology, University of Greifswald, Greifswald, Germany.

    • Rainer Rettig
  64. DZD (German Center for Diabetes Research), site Greifswald, Greifswald, Germany.

    • Henry Völzke
  65. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Henry Völzke
  66. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.

    • Wen-Jane Lee
  67. Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.

    • I-Te Lee
    •  & Wayne H-H Sheu
  68. School of Medicine, National Yang-Ming University, Taipei, Taiwan.

    • I-Te Lee
    •  & Wayne H-H Sheu
  69. School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

    • I-Te Lee
  70. Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan.

    • Wayne H-H Sheu
  71. School of Medicine, National Defense Medical Center, Taipei, Taiwan.

    • Wayne H-H Sheu
  72. Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Digna R Velez Edwards
  73. Epidemiology and Prevention Center for Genomics and Personalized Medicine Research, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  74. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Adolfo Correa
  75. Harvard Medical School, Boston, Massachusetts, USA.

    • Paul M Ridker
    •  & Daniel I Chasman
  76. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Alexander P Reiner
    •  & Bruce M Psaty
  77. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Todd L Edwards
  78. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.

    • Jerome I Rotter
  79. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  80. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Bruce M Psaty
  81. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  82. Cardiology, Geneva University Hospitals, Geneva, Switzerland.

    • Georg B Ehret
  83. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh

Consortia

  1. CHD Exome+ Consortium

    A list of members and affiliations appears in the Supplementary Note

  2. ExomeBP Consortium

    A list of members and affiliations appears in the Supplementary Note

  3. GoT2DGenes Consortium

    A list of members and affiliations appears in the Supplementary Note

  4. T2D-GENES Consortium

    A list of members and affiliations appears in the Supplementary Note

  5. Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia

    A list of members and affiliations appears in the Supplementary Note

  6. CKDGen Consortium

    A list of members and affiliations appears in the Supplementary Note

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Contributions

Study design: A.T.K., C.L., N.F., G.B.E., C.N.-C., J.I.R., B.M.P., D.L., D.I.C. Phenotyping: E.B., V.G., B.M.P., D.L., D.R.W., A. Correa, A. Chakravarti, W.P., M.D., R.R., W.H.-H.S., P.M.R., A.P.R., J.E.R., C.K., N.F., K.L., C.B., Y.-D.I.C., A.T.K., M.G.L., L.J.R., E.P.B., O.G., H.V., W.-J.L., J.I.R., O.H.F., R.S.V., R.J.F.L., A. Correa, A. Chakravarti, T.L.E., I.-T.L., L.W.M., G.J.P. Genotyping: E.B., D.L., A.P.R., C.K., Y.-D.I.C., M.F., C.J.O'D., S.L.R.K., U.V., D.I.C., C.N.-C., J.A.B., J.C.B., E.W.D., K.D.T., C.L., J.A.S., W.Z., J.D.F., Y.-D.I.C., S.W., E.K., A.G.U., A.Y.C., J.I.R., B.M.P., D.R.V.E., Y. Liu, C.M.v.D., I.B.B., R.J.F.L., L.J.L., T.B.H., T.L.E., S.B.F., F.G., P.L.A., M.L.G. Quality control: A.P.R., D.I.C., C.N.-C., J.A.B., J.C.B., E.W.D., K.D.T., C.L., S.-J.H., J.A.S., W.Z., J.D.F., S.W., A.Y.C., F.G., P.L.A., M.L.G., M.D., H.V., G.B.E., A.C.M., J.J., A.V.S., L. Lin. Software development: J.A.B., C.L., A.Y.C., F.G., P.L.A., A.T.K., K.R., A.V., H.C., D.I.C. Statistical analysis: A.P.R., D.I.C., C.N.-C., G.K., J.A.B., J.C.B., C.L., Y. Lu, J.A.S., W.Z., J.D.F., S.W., A.Y.C., F.G., P.L.A., G.B.E., A.C.M., J.J., A.V.S., L. Lin, J.M.S., N.A., K.S.T., T.H., A.G., C.K., N.F., A.T.K., M.G.L., S.G., E.S., K.R., H.M., X.G., J.Y., P.S., F.D., J.P.C., S.K., N.O.S., H.S., P.D., N.S., C.F., M.G., M.L., C.P. Manuscript writing: C.L., A.T.K., J.A.S., N.F., J.C.B., Y. Lu, W.P., L.W.M., M.G.L., K.R., T.L.E., M.F., G.B.E., J.I.R., C.N.-C., D.L., D.I.C.

Competing interests

B.M.P. serves on the DSMB for 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. The other authors declare no competing financial interests.

Corresponding authors

Correspondence to Chunyu Liu or Daniel Levy or Daniel I Chasman.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3, Supplementary Tables 7–20 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    CHARGE+ Exome Chip BP Consortium: experiment-wide significant associations in meta-analysis.

  2. 2.

    Supplementary Table 2

    CHARGE+ Exome Chip BP Consortium: associations with P < 1 × 10−4 in samples of all ancestries.

  3. 3.

    Supplementary Table 3

    CHARGE+ Exome Chip BP Consortium: previously identified GWAS loci with P < 0.001 for any blood pressure trait.

  4. 4.

    Supplementary Table 4

    Meta-analysis of the discovery and follow-up samples of European ancestry: associations with P < 3.4 × 10−7.

  5. 5.

    Supplementary Table 5

    Meta-analysis of the discovery and follow-up samples of all ancestries: associations with P < 3.4 × 10−7.

  6. 6.

    Supplementary Table 6

    CHARGE+ Exome Chip BP Consortium: effects of the coded alleles on the five blood pressure traits in all ancestries.

  7. 7.

    Supplementary Table 21

    Exome Chip genotyping, data cleaning, and quality control.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3660

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