Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 240 novel loci

Mosaic loss of chromosome Y (mLOY) is the most commonly detected mosaic chromosomal alteration, and is associated with a range of health outcomes in males. We detected mLOY in 106,054 European (EUR), 13,927 admixed African (AFR), and 6,127 Hispanic (HIS) participants of the Million Veteran Program (MVP; Ntotal=544,112). mLOY was positively associated with cigarette smoking, and negatively with obesity and type 2 diabetes. Multi-ancestry genome-wide association meta-analysis of MVP and UK Biobank mLOY summary statistics, jointly comprising 167,899 cases and 581,224 controls, identified 380 independent risk loci—240 of which were novel. GWAS in MVP high cell fraction (CF>10%) mLOY cases exhibited stronger effect sizes across risk loci. Local-ancestry-aware GWAS resolved ancestry-specific signals at BCL2L1 and SETBP1. Integrative eQTL analyses highlighted 51 genes that causally influence mLOY via differential expression. Finally, traits with genetic correlations and polygenic scores significantly associated with mLOY were selected for Mendelian randomization (MR), implicating thirteen traits as causal influences on mLOY, including triglycerides, high-density lipoprotein, and body mass index.