Title: GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation.
Authors: 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
Published In Nat Commun, (2019 10 17)
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.
PubMed ID: 31624269
MeSH Terms: Aged; Aged, 80 and over; Asian Continental Ancestry Group/genetics; Blood Platelets/cytology; Blood Platelets/metabolism; Cell Differentiation/genetics*; Chromosome Deletion*; Chromosomes, Human, Y/genetics*; Cohort Studies; Erythrocytes/cytology; Erythrocytes/metabolism; Genetic Predisposition to Disease/ethnology; Genetic Predisposition to Disease/genetics; Genome-Wide Association Study/methods*; Genotype; Hematopoietic Stem Cells/cytology; Hematopoietic Stem Cells/metabolism*; Humans; Japan; Male; Mosaicism; Polymorphism, Single Nucleotide