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Nat Commun. 2019 Oct 17;10(1):4719. doi: 10.1038/s41467-019-12705-5.

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

Author information

1
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan. chikashi.terao@riken.jp.
2
Clinical Research Center, Shizuoka General Hospital, Shizuoka, 420-8527, Japan. chikashi.terao@riken.jp.
3
The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan. chikashi.terao@riken.jp.
4
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
5
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan.
6
Healthcare and Medical Data Driven AI based Predictive Reasoning Development Unit, Medical Sciences Innovation Hub Program (MIH), RIKEN, Kanagawa, 230-0045, Japan.
7
Laboratory for Developmental Genetics, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama, Kanagawa, 230-0045, Japan.
8
Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.
9
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
10
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
11
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
12
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
13
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
14
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science (IMS), Yokohama, Kanagawa, 230-0045, Japan.
15
Database Center for Life Science, Joint Support-Center for Data Science Research, Research Organization of Information and Systems, Mishima, Shizuoka, 411-8540, Japan.
16
Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
17
MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK.
18
Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan.
19
Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
20
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan. yoichiro.kamatani@riken.jp.
21
Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan. yoichiro.kamatani@riken.jp.

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.

PMID:
31624269
PMCID:
PMC6797717
DOI:
10.1038/s41467-019-12705-5
[Indexed for MEDLINE]
Free PMC Article

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