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

Chikashi Terao (), Yukihide Momozawa, Kazuyoshi Ishigaki, Eiryo Kawakami, Masato Akiyama, Po-Ru Loh, Giulio Genovese, Hiroki Sugishita, Tazro Ohta, Makoto Hirata, John R. B. Perry, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo and Yoichiro Kamatani ()
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Chikashi Terao: Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences
Yukihide Momozawa: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences
Kazuyoshi Ishigaki: Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences
Eiryo Kawakami: Healthcare and Medical Data Driven AI based Predictive Reasoning Development Unit, Medical Sciences Innovation Hub Program (MIH), RIKEN
Masato Akiyama: Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences
Po-Ru Loh: Brigham and Women’s Hospital and Harvard Medical School
Giulio Genovese: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Hiroki Sugishita: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science (IMS)
Tazro Ohta: Database Center for Life Science, Joint Support-Center for Data Science Research, Research Organization of Information and Systems
Makoto Hirata: The University of Tokyo
John R. B. Perry: University of Cambridge
Koichi Matsuda: The University of Tokyo
Yoshinori Murakami: The University of Tokyo
Michiaki Kubo: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences
Yoichiro Kamatani: Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12705-5

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