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

Author

Listed:
  • Chikashi Terao

    (Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences
    Clinical Research Center, Shizuoka General Hospital
    University of Shizuoka)

  • 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
    Laboratory for Developmental Genetics, Center for Integrative Medical Sciences (IMS), RIKEN
    Chiba University)

  • Masato Akiyama

    (Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences
    Kyushu University)

  • Po-Ru Loh

    (Brigham and Women’s Hospital and Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Giulio Genovese

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Department of Genetics, Harvard Medical School
    Stanley Center for Psychiatric Research, 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
    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
    The University of Tokyo)

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.

Suggested Citation

  • 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 Mats, 2019. "GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12705-5
    DOI: 10.1038/s41467-019-12705-5
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    Cited by:

    1. Derek W. Brown & Liam D. Cato & Yajie Zhao & Satish K. Nandakumar & Erik L. Bao & Eugene J. Gardner & Aubrey K. Hubbard & Alexander DePaulis & Thomas Rehling & Lei Song & Kai Yu & Stephen J. Chanock &, 2023. "Shared and distinct genetic etiologies for different types of clonal hematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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