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GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation

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Terao, Chikashi 
Momozawa, Yukihide 
Ishigaki, Kazuyoshi 
Kawakami, Eiryo 
Akiyama, Masato 


Mosaic 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.



Aged, Aged, 80 and over, Asian People, Blood Platelets, Cell Differentiation, Chromosome Deletion, Chromosomes, Human, Y, Cohort Studies, Erythrocytes, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hematopoietic Stem Cells, Humans, Japan, Male, Mosaicism, Polymorphism, Single Nucleotide

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Nature Communications

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Springer Nature
Medical Research Council (MC_UU_12015/2)
This 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.