Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program
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Published:2022-12-08
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Wheeler Marsha M., Stilp Adrienne M.ORCID, Rao Shuquan, Halldórsson Bjarni V.ORCID, Beyter DorukORCID, Wen JiaORCID, Mihkaylova Anna V.ORCID, McHugh Caitlin P., Lane John, Jiang Min-ZhiORCID, Raffield Laura M., Jun Goo, Sedlazeck Fritz J.ORCID, Metcalf Ginger, Yao Yao, Bis Joshua B.ORCID, Chami NathalieORCID, de Vries Paul S., Desai Pinkal, Floyd James S., Gao Yan, Kammers Kai, Kim WonjiORCID, Moon Jee-Young, Ratan Aakrosh, Yanek Lisa R.ORCID, Almasy Laura, Becker Lewis C., Blangero JohnORCID, Cho Michael H.ORCID, Curran Joanne E.ORCID, Fornage MyriamORCID, Kaplan Robert C., Lewis Joshua P.ORCID, Loos Ruth J. F.ORCID, Mitchell Braxton D., Morrison Alanna C.ORCID, Preuss MichaelORCID, Psaty Bruce M.ORCID, Rich Stephen S.ORCID, Rotter Jerome I., Tang HuaORCID, Tracy Russell P., Boerwinkle Eric, Abecasis Goncalo R., Blackwell Thomas W., Smith Albert V.ORCID, Johnson Andrew D.ORCID, Mathias Rasika A.ORCID, Nickerson Deborah A., Conomos Matthew P.ORCID, Li Yun, Þorsteinsdóttir Unnur, Magnússon Magnús K.ORCID, Stefansson Kari, Pankratz Nathan D.ORCID, Bauer Daniel E.ORCID, Auer Paul L.ORCID, Reiner Alex P.ORCID
Abstract
AbstractGenome-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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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