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.
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,"GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation",Nature Communications,10.1038/s41467-019-12705-5