| Title: | GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation |
| Journal: | Nature Communications |
| Published: | 17 Oct 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31624269/ |
| DOI: | https://doi.org/10.1038/s41467-019-12705-5 |
| URL: | https://www.nature.com/articles/s41467-019-12705-5.pdf |
Publication 9043
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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.</p>
15 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 19808 | Exploring large-scale genetic mosaicism and its relationship to hematological malignancies |
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