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Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program

Author

Listed:
  • Marsha M. Wheeler

    (University of Washington)

  • Adrienne M. Stilp

    (University of Washington)

  • Shuquan Rao

    (Boston Children’s Hospital
    Dana-Farber Cancer Institute
    Harvard Stem Cell Institute
    Broad Institute)

  • Bjarni V. Halldórsson

    (deCODE genetics/Amgen Inc.
    Reykjavik University)

  • Doruk Beyter

    (deCODE genetics/Amgen Inc.)

  • Jia Wen

    (University of North Carolina at Chapel Hill)

  • Anna V. Mihkaylova

    (University of Washington)

  • Caitlin P. McHugh

    (University of Washington)

  • John Lane

    (University of Minnesota Medical School)

  • Min-Zhi Jiang

    (University of North Carolina at Chapel Hill)

  • Laura M. Raffield

    (University of North Carolina)

  • Goo Jun

    (The University of Texas Health Science Center at Houston)

  • Fritz J. Sedlazeck

    (Baylor College of Medicine)

  • Ginger Metcalf

    (Baylor College of Medicine)

  • Yao Yao

    (Boston Children’s Hospital
    Dana-Farber Cancer Institute
    Harvard Stem Cell Institute
    Broad Institute)

  • Joshua B. Bis

    (University of Washington)

  • Nathalie Chami

    (Icahn School of Medicine at Mount Sinai)

  • Paul S. Vries

    (The University of Texas Health Science Center at Houston
    The University of Texas Health Science Center at Houston)

  • Pinkal Desai

    (Weill Cornell Medical College)

  • James S. Floyd

    (University of Washington)

  • Yan Gao

    (University of Mississippi)

  • Kai Kammers

    (Johns Hopkins University School of Medicine)

  • Wonji Kim

    (Brigham and Women’s Hospital)

  • Jee-Young Moon

    (Albert Einstein College of Medicine)

  • Aakrosh Ratan

    (University of Virginia)

  • Lisa R. Yanek

    (Johns Hopkins University School of Medicine)

  • Laura Almasy

    (Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine)

  • Lewis C. Becker

    (Johns Hopkins University School of Medicine)

  • John Blangero

    (University of Texas Rio Grande Valley School of Medicine)

  • Michael H. Cho

    (Brigham and Women’s Hospital)

  • Joanne E. Curran

    (University of Texas Rio Grande Valley School of Medicine)

  • Myriam Fornage

    (University of Texas Health Science Center at Houston)

  • Robert C. Kaplan

    (Albert Einstein College of Medicine)

  • Joshua P. Lewis

    (University of Maryland School of Medicine)

  • Ruth J. F. Loos

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    University of Copenhagen)

  • Braxton D. Mitchell

    (University of Maryland School of Medicine)

  • Alanna C. Morrison

    (The University of Texas Health Science Center at Houston)

  • Michael Preuss

    (Icahn School of Medicine at Mount Sinai)

  • Bruce M. Psaty

    (University of Washington)

  • Stephen S. Rich

    (University of Virginia)

  • Jerome I. Rotter

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Hua Tang

    (Stanford University School of Medicine)

  • Russell P. Tracy

    (Larner College of Medicine at the University of Vermont)

  • Eric Boerwinkle

    (The University of Texas Health Science Center at Houston)

  • Goncalo R. Abecasis

    (University of Michigan, Department of Biostatistics)

  • Thomas W. Blackwell

    (University of Michigan, Department of Biostatistics)

  • Albert V. Smith

    (University of Michigan, Department of Biostatistics)

  • Andrew D. Johnson

    (National Heart, Lung and Blood Institute)

  • Rasika A. Mathias

    (Johns Hopkins University School of Medicine)

  • Deborah A. Nickerson

    (University of Washington)

  • Matthew P. Conomos

    (University of Washington)

  • Yun Li

    (University of North Carolina at Chapel Hill)

  • Unnur Þorsteinsdóttir

    (deCODE genetics/Amgen Inc.
    University of Iceland)

  • Magnús K. Magnússon

    (deCODE genetics/Amgen Inc.
    University of Iceland)

  • Kari Stefansson

    (deCODE genetics/Amgen Inc.
    University of Iceland)

  • Nathan D. Pankratz

    (University of Minnesota Medical School)

  • Daniel E. Bauer

    (Boston Children’s Hospital
    Dana-Farber Cancer Institute
    Harvard Stem Cell Institute
    Broad Institute)

  • Paul L. Auer

    (Medical College of Wisconsin)

  • Alex P. Reiner

    (University of Washington)

Abstract

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

Suggested Citation

  • Marsha M. Wheeler & Adrienne M. Stilp & Shuquan Rao & Bjarni V. Halldórsson & Doruk Beyter & Jia Wen & Anna V. Mihkaylova & Caitlin P. McHugh & John Lane & Min-Zhi Jiang & Laura M. Raffield & Goo Jun , 2022. "Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35354-7
    DOI: 10.1038/s41467-022-35354-7
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    References listed on IDEAS

    as
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