American journal of human genetics · 2025

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

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Jakubek Yasminka A, Ma Xiaolong, Stilp Adrienne M, Yu Fulong, Bacon Jason, Wong Justin W, Aguet Francois, Ardlie Kristin, Arnett Donna K, Barnes Kathleen, Bis Joshua C, Blackwell Tom, Becker Lewis C, Boerwinkle Eric, Bowler Russell P, Budoff Matthew J, Carson April P, Chen Jiawen, Cho Michael H, Coresh Josef, Cox Nancy J, de Vries Paul S, DeMeo Dawn L, Fardo David W, Fornage Myriam, Guo Xiuqing, Hall Michael E, Heard-Costa Nancy, Hidalgo Bertha, Irvin Marguerite Ryan, Johnson Andrew D, Jorgenson Eric, Kenny Eimear E, Kessler Michael D, Levy Daniel, Li Yun, Lima Joao A C, Liu Yongmei, Locke Adam E, Loos Ruth J F, Machiela Mitchell J, Mathias Rasika A, Mitchell Braxton D, Murabito Joanne M, Mychaleckyj Josyf C, North Kari E, Orchard Peter, Parker Stephen C J, Pershad Yash, Peyser Patricia A, Pratte Katherine A, Psaty Bruce M, Raffield Laura M, Redline Susan, Regeneron Genetics Center, Rich Stephen S, Rotter Jerome I, Shah Sanjiv J, Smith Jennifer A, Smith Aaron P, Smith Albert, Taub Margaret A, Tiwari Hemant K, Tracy Russell, Tuftin Bjoernar, NHLBI Trans-Omics for Precision Medicine Consortium, Bick Alexander G, Sankaran Vijay G, Reiner Alexander P, Scheet Paul, Auer Paul L

Аннотация

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.

Предметные рубрики MeSH

Humans Chromosomes, Human, Y Male Mosaicism Phenotype Haplotypes Whole Genome Sequencing Genomics Chromosome Deletion Polymorphism, Single Nucleotide Genome, Human

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

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Аннотация

Предметные рубрики MeSH