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dc.contributor.authorTerao, Chikashien
dc.contributor.authorMomozawa, Yukihideen
dc.contributor.authorIshigaki, Kazuyoshien
dc.contributor.authorKawakami, Eiryoen
dc.contributor.authorAkiyama, Masatoen
dc.contributor.authorLoh, Po-Ruen
dc.contributor.authorGenovese, Giulioen
dc.contributor.authorSugishita, Hirokien
dc.contributor.authorOhta, Tazroen
dc.contributor.authorHirata, Makotoen
dc.contributor.authorPerry, Johnen
dc.contributor.authorMatsuda, Koichien
dc.contributor.authorMurakami, Yoshinorien
dc.contributor.authorKubo, Michiakien
dc.contributor.authorKamatani, Yoichiroen
dc.description.abstractMosaic loss of chromosome Y (mLOY) is frequently observed in the leukocytes of ageing men. However, the genetic architecture and biological mechanisms underlying mLOY are not fully understood. In a cohort of 95,380 Japanese men, we identify 50 independent genetic markers in 46 loci associated with mLOY at a genome-wide significant level, 35 of which are unreported. Lead markers overlap enhancer marks in hematopoietic stem cells (HSCs, P ≤ 1.0 × 10−6). mLOY genome-wide association study signals exhibit polygenic architecture and demonstrate strong heritability enrichment in regions surrounding genes specifically expressed in multipotent progenitor (MPP) cells and HSCs (P ≤ 3.5 × 10−6). ChIP-seq data demonstrate that binding sites of FLI1, a fate-determining factor promoting HSC differentiation into platelets rather than red blood cells (RBCs), show a strong heritability enrichment (P = 1.5 × 10−6). Consistent with these findings, platelet and RBC counts are positively and negatively associated with mLOY, respectively. Collectively, our observations improve our understanding of the mechanisms underlying mLOY.
dc.description.sponsorshipThis research was conducted using the UK Biobank Resource under Application #19808. P.-R.L. was supported by NIH grant DP2 ES030554, a Burroughs Wellcome Fund Career Award at the Scientific Interfaces, the Next Generation Fund at the Broad Institute of MIT and Harvard, and a Glenn Foundation for Medical Research and AFAR Grants for Junior Faculty award. G.G. was supported by US Department of Defense Breast Cancer Research Breakthrough Award W81XWH-16-1-0316 and the Stanley Center for Psychiatric Research.
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.titleGWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiationen
prism.publicationNameNature Communicationsen
dc.contributor.orcidPerry, John [0000-0001-6483-3771]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_UU_12015/2)

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International