Abstract

The increasing volume of whole-genome sequence (WGS) and multi-omics data requires new approaches for analysis. As one solution, we have created the cloud-based Analysis Commons, which brings together genotype and phenotype data from multiple studies in a setting that is accessible by multiple investigators. This framework addresses many of the challenges of multicenter WGS analyses, including data-sharing mechanisms, phenotype harmonization, integrated multi-omics analyses, annotation and computational flexibility. In this setting, the computational pipeline facilitates a sequence-to-discovery analysis workflow illustrated here by an analysis of plasma fibrinogen levels in 3,996 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) WGS program. The Analysis Commons represents a novel model for translating WGS resources from a massive quantity of phenotypic and genomic data into knowledge of the determinants of health and disease risk in diverse human populations.

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Acknowledgements

TOPMed. WGS for the TOPMed program was supported by the NHLBI. WGS for 'NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study' (phs000974.v1.p1) and 'NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish' (phs000956.v1.p1) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C and 3R01HL121007-01S1 (NHLBI, B.D.M.)). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity quality control and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1 (NHLBI, B.M.P., K.M.R. and S.S.R.)). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The infrastructure for the Analysis Commons is additionally supported by R01HL105756 (NHLBI, B.M.P.), U01HL130114 (NHLBI, B.M.P.) and 5RC2HL102419 (NHLBI, E.B.).

Old Order Amish Study. This investigation was supported by National Institutes of Health grants R01 HL121007 (NHLBI, B.D.M.), U01 GM074518, U01 HL084756 (NHLBI, J.R.O.), U01 HL137181 (NHLBI, J.R.O.) and K23 GM102678 (NIGMS, J.P.L.), as well as Mid-Atlantic Nutrition and Obesity Research Center grant P30 DK072488 (NIDDK, B.D.M.). We also gratefully acknowledge our Amish liaisons and field workers and the extraordinary cooperation and support of the Amish community.

Framingham Heart Study. The Framingham Heart Study was supported by the NHLBI Framingham Heart Study (contract no. N01-HC-25195 and HHSN268201500001I (NHLBI, R.S.V. and L.A.C.)), Fibrinogen measurement was supported by NIH R01-HL-48157. J.E.H. and A.D.J. were supported by NHLBI Intramural Research Program funds. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI, the National Institutes of Health or the US Department of Health and Human Services.

Author information

Author notes

    • Jennifer A Brody
    • , Alanna C Morrison
    •  & Joshua C Bis

    These authors contributed equally to this work.

    • Eric Boerwinkle
    • , Bruce M Psaty
    •  & L Adrienne Cupples

    These authors jointly directed this work.

Affiliations

  1. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Jennifer A Brody
    • , Joshua C Bis
    • , Colleen M Sitlani
    • , Nicholas L Smith
    • , Susan R Heckbert
    •  & Bruce M Psaty
  2. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Alanna C Morrison
    • , Michael R Brown
    • , Xiaoming Liu
    •  & Eric Boerwinkle
  3. Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland, Baltimore, Maryland, USA.

    • Jeffrey R O'Connell
    • , Joshua P Lewis
    •  & Braxton D Mitchell
  4. Framingham Heart Study, National Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts, USA.

    • Jennifer E Huffman
    • , Andrew D Johnson
    • , Achilleas N Pitsillides
    • , Ramachandran S Vasan
    •  & L Adrienne Cupples
  5. DNAnexus, Inc. Mountain View, California, USA.

    • Darren C Ames
    •  & Andrew Carroll
  6. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Matthew P Conomos
    • , Stephanie M Gogarten
    • , Kenneth M Rice
    •  & Cathy C Laurie
  7. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Stacey Gabriel
    •  & Namrata Gupta
  8. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • Richard A Gibbs
    • , William Salerno
    •  & Eric Boerwinkle
  9. National Heart, Lung, and Blood Institute, Division of Cardiovascular Sciences, Bethesda, Maryland, USA.

    • Cashell E Jaquish
    •  & George J Papanicolaou
  10. Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Alisa K Manning
  11. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Alisa K Manning
  12. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Alisa K Manning
  13. Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.

    • Nicholas L Smith
    •  & Bruce M Psaty
  14. Seattle Epidemiologic Research and Information Center, Department of Veteran Affairs Office of Research and Development, Seattle, Washington, USA.

    • Nicholas L Smith
  15. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Nicholas L Smith
    •  & Susan R Heckbert
  16. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Braxton D Mitchell
  17. Sections of Preventive Medicine and Epidemiology, and of Cardiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
  18. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
  19. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Stephen S Rich
  20. Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor -UCLA Medical Center, Torrance, California, USA.

    • Jerome I Rotter
  21. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • James G Wilson
  22. Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  23. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • L Adrienne Cupples

Consortia

  1. NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

    A full list of members and affiliations appears in the Supplementary Note.

  2. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

    A full list of members and affiliations appears in the Supplementary Note.

  3. TOPMed Hematology and Hemostasis Working Group

    A full list of members and affiliations appears in the Supplementary Note.

  4. CHARGE Analysis and Bioinformatics Working Group

    A full list of members and affiliations appears in the Supplementary Note.

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Competing interests

B.M.P. reports serving on the data and safety monitoring board for a clinical trial funded by the manufacturer Zoll LifeCor and on the Steering Committee for the Yale Open Data Access Project funded by Johnson & Johnson. J.R.O. has a consulting agreement with Regeneron Pharmaceuticals that focuses on development of statistical analysis and software tools. A.C. and D.C.A. are employed by DNAnexus.

Corresponding authors

Correspondence to Jennifer A Brody or L Adrienne Cupples.

Supplementary information

PDF files

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    Supplementary Text and Figures

    Supplementary Note