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 language | English |
|---|---|
| Article number | 4719 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 01-12-2019 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
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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 journal › Article
TY - JOUR
T1 - GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation
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
Y1 - 2019/12/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073514300&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073514300&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12705-5
DO - 10.1038/s41467-019-12705-5
M3 - Article
C2 - 31624269
AN - SCOPUS:85073514300
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4719
ER -