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, Yoichiro Kamatani

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number4719
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 01-12-2019

Fingerprint

blood cells
Y Chromosome
Genome-Wide Association Study
chromosomes
Chromosomes
Cell Differentiation
Blood Cells
Blood
Cells
genome
Genes
erythrocytes
Platelets
platelets
markers
Blood Platelets
blood cell count
leukocytes
Erythrocyte Count
stem cells

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Terao, C., Momozawa, Y., Ishigaki, K., Kawakami, E., Akiyama, M., Loh, P. R., ... Kamatani, Y. (2019). GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation. Nature Communications, 10(1), [4719]. https://doi.org/10.1038/s41467-019-12705-5
Terao, Chikashi ; Momozawa, Yukihide ; Ishigaki, Kazuyoshi ; Kawakami, Eiryo ; Akiyama, Masato ; Loh, Po Ru ; Genovese, Giulio ; Sugishita, Hiroki ; Ohta, Tazro ; Hirata, Makoto ; Perry, John R.B. ; Matsuda, Koichi ; Murakami, Yoshinori ; Kubo, Michiaki ; Kamatani, Yoichiro. / GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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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.",
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Terao, C, Momozawa, Y, Ishigaki, K, Kawakami, E, Akiyama, M, Loh, PR, Genovese, G, Sugishita, H, Ohta, T, Hirata, M, Perry, JRB, Matsuda, K, Murakami, Y, Kubo, M & Kamatani, Y 2019, 'GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation', Nature Communications, vol. 10, no. 1, 4719. https://doi.org/10.1038/s41467-019-12705-5

GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation. / Terao, Chikashi; Momozawa, Yukihide; Ishigaki, Kazuyoshi; Kawakami, Eiryo; Akiyama, Masato; Loh, Po Ru; Genovese, Giulio; Sugishita, Hiroki; Ohta, Tazro; Hirata, Makoto; Perry, John R.B.; Matsuda, Koichi; Murakami, Yoshinori; Kubo, Michiaki; Kamatani, Yoichiro.

In: Nature Communications, Vol. 10, No. 1, 4719, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Terao, Chikashi

AU - Momozawa, Yukihide

AU - Ishigaki, Kazuyoshi

AU - Kawakami, Eiryo

AU - Akiyama, Masato

AU - Loh, Po Ru

AU - Genovese, Giulio

AU - Sugishita, Hiroki

AU - Ohta, Tazro

AU - Hirata, Makoto

AU - Perry, John R.B.

AU - Matsuda, Koichi

AU - Murakami, Yoshinori

AU - Kubo, Michiaki

AU - Kamatani, Yoichiro

PY - 2019/12/1

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N2 - 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.

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