Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 167 novel loci

Abstract

AbstractMosaic loss of chromosome Y (mLOY) is a common somatic mutation in leukocytes of older males. mLOY was detected in 126,108 participants of the Million Veteran Program: 106,054 European (EUR), 13,927 admixed African (AFR), and 6,127 Hispanic. In multi-ancestry genome-wide association analysis, we identified 323 genome-wide significant loci, 167 of which were novel–more than doubling the number of known mLOY loci. Tract-based ancestry deconvolution resolved local inflation at AFR lead SNPs. Transcriptome-wide associations yielded 2,297 significant genes, including seven additional novel genes; integrative eQTL analyses highlighted 51 genes that causally influence mLOY via differential expression. Thirty-two significant traits found in a phenome-wide polygenic score scan were used in Mendelian randomization (MR). MR implicated six traits as causal influences on mLOY: triglycerides, high-density lipoprotein, smoking, body mass index, testosterone, and sex hormone-binding globulin; and found influence of mLOY on plateletcrit, prostate cancer, lymphocyte percentage, and neutrophil percentage. These results mark a major step forward in our understanding of the genetic architecture of mLOY and its associated risks.