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

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, Fritz J. Sedlazeck, Ginger Metcalf, Yao Yao, Joshua B. Bis, Nathalie Chami, Paul S. Vries, Pinkal Desai, James S. Floyd, Yan Gao, Kai Kammers, Wonji Kim, Jee-Young Moon, Aakrosh Ratan, Lisa R. Yanek, Laura Almasy, Lewis C. Becker, John Blangero, Michael H. Cho, Joanne E. Curran, Myriam Fornage, Robert C. Kaplan, Joshua P. Lewis, Ruth J. F. Loos, Braxton D. Mitchell, Alanna C. Morrison, Michael Preuss, Bruce M. Psaty, Stephen S. Rich, Jerome I. Rotter, Hua Tang, Russell P. Tracy, Eric Boerwinkle, Goncalo R. Abecasis, Thomas W. Blackwell, Albert V. Smith, Andrew D. Johnson, Rasika A. Mathias, Deborah A. Nickerson, Matthew P. Conomos, Yun Li, Unnur Þorsteinsdóttir, Magnús K. Magnússon, Kari Stefansson, Nathan D. Pankratz, Daniel E. Bauer, Paul L. Auer () and Alex P. Reiner ()
Additional contact information
Marsha M. Wheeler: University of Washington
Adrienne M. Stilp: University of Washington
Shuquan Rao: Boston Children’s Hospital
Bjarni V. Halldórsson: deCODE genetics/Amgen Inc.
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
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
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
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.
Magnús K. Magnússon: deCODE genetics/Amgen Inc.
Kari Stefansson: deCODE genetics/Amgen Inc.
Nathan D. Pankratz: University of Minnesota Medical School
Daniel E. Bauer: Boston Children’s Hospital
Paul L. Auer: Medical College of Wisconsin
Alex P. Reiner: University of Washington

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35354-7

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