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

Mosaic 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. ### Competing Interest Statement A.G.B. is on the scientific advisory board of TenSixteen Bio unrelated to the present work. P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. D.K. is a scientific advisor and reports consulting fees from Bitterroot Bio, Inc unrelated to the present work. The other authors declare no competing interests. ### Funding Statement This study was funded by the Department of Veterans Affairs Office of Research & Development Million Veteran Program (MVP) award #000. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Central IRB of the VA Office of Research & Development gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The full summary level association data from the meta-analysis and individual population association analyses in MVP will be available via the dbGaP study accession number phs001672. Full transcriptome-wide association study results are available upon request.