Author:
Jakubek Yasminka A.,Ma Xiaolong,Stilp Adrienne M.,Yu Fulong,Bacon Jason,Wong Justin W.,Aguet Francois,Ardlie Kristin,Arnett Donna,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,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.,Kenny Eimear E.,Levy Dan,Li Yun,Lima Joao AC.,Liu Yongmei,Loos Ruth J.F.,Machiela Mitchell J.,Mathias Rasika A.,Mitchell Braxton D.,Murabito Joanne,Mychaleckyj Josyf C.,North Kari,Orchard Peter,Parker Stephen CJ.,Pershad Yash,Peyser Patricia A.,Pratte Katherine A.,Psaty Bruce M.,Raffield Laura M.,Redline Susan,Rich Stephen S.,Rotter Jerome I.,Shah Sanjiv J.,Smith Jennifer A.,Smith Aaron P.,Smith Albert,Taub Margaret,Tiwari Hemant K.,Tracy Russell,Tuftin Bjoernar,Bick Alexander G.,Sankaran Vijay G.,Reiner Alexander P.,Scheet Paul,Auer Paul L.
Abstract
AbstractMosaic 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’s 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 of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. 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 American (EA) ancestry group compared to those of Hispanic American (HA), African American (AA), and East Asian (EAS) ancestry. Further, we identified two genes (CFHR1andLRP6) that harbor multiple rare, putatively deleterious variants associated with mLOY susceptibility, show that subsets of human hematopoietic stem cells are enriched for activity of mLOY susceptibility variants, and that certain alleles on chromosome Y are more likely to be lost than others.
Publisher
Cold Spring Harbor Laboratory