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

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’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 ( CFHR1 and LRP6 ) 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. ### Competing Interest Statement L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (through Westat). A.G.B. is on the scientific advisory board of TenSixteen Bio unrelated to the present work. P.L.A. serves on the board of Geno.Me Inc. V.G.S. serves as an advisor and/or has equity in Branch Biosciences, Ensoma, and Cellarity, all unrelated to the present work. The remaining authors declare no competing interests. ### Funding Statement Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL11762602S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL120393; U01HL120393; contract HHSN268201800001I). Amish: The TOPMed component of the Amish Research Program was supported by NIH grants R01 HL121007, U01 HL072515, and R01 AG18728. ARIC: The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). BAGS: Funding for BAGS was provided by National Institutes of Health (NIH) R01HL104608, R01HL087699, and HL104608 S1. BioMe: The Mount Sinai BioMe Biobank has been supported by The Andrea and Charles Bronfman Philanthropies and in part by Federal funds from the NHLBI and NHGRI (U01HG00638001; U01HG007417; X01HL134588). CARDIA: The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201800005I & HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). CARDIA was also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra‐agency agreement between NIA and NHLBI (AG0005). CFS: The Cleveland Family Study has been supported in part by National Institutes of Health grants [R01HL046380, KL2RR024990, R35HL135818, and R01HL113338]. CHS: This Cardiovascular Health Study research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). COPDGene: The COPDGene project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. FHS: The Framingham Heart Study (FHS) acknowledges the support of contracts NO1HC25195 and HHSN268201500001I from the National Heart, Lung and Blood Institute and grant supplement R01 HL09257706S1 for this research. GeneSTAR: GeneSTAR was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (U01 HL72518, HL087698, HL112064, HL11006, HL118356) and by a grant from the National Institutes of Health/National Center for Research Resources (M01RR000052) to the Johns Hopkins General Clinical Research Center. GENOA: Support for GENOA was provided by the National Heart, Lung and Blood Institute (U01 HL054457, U01 HL054464, U01 HL054481, R01 HL119443, and R01 HL087660) of the National Institutes of Health. GOLDN: GOLDN biospecimens, baseline phenotype data, and intervention phenotype data were collected with funding from National Heart, Lung and Blood Institute (NHLBI) grant U01 HL072524. Whole-genome sequencing in GOLDN was funded by NHLBI grant R01 HL104135 and supplement R01 HL10413504S1. HCHS/SOL: The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (HHSN268201300001I / N01HC65233), University of Miami (HHSN268201300004I / N01HC65234), Albert Einstein College of Medicine (HHSN268201300002I / N01HC65235), University of Illinois at Chicago HHSN268201300003I / N01HC65236 Northwestern Univ), and San Diego State University (HHSN268201300005I / N01HC65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution Office of Dietary Supplements. HyperGEN: The HyperGEN Study is part of the National Heart, Lung, and Blood Institute (NHLBI) Family Blood Pressure Program; collection of the data represented here was supported by grants U01 HL054472 (MN Lab), U01 HL054473 (DCC), U01 HL054495 (AL FC), and U01 HL054509 (NC FC). The HyperGEN: Genetics of Left Ventricular Hypertrophy Study was supported by NHLBI grant R01 HL055673 with whole,genome sequencing made possible by supplement 18S1. JHS: The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). MESA: Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA) (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL11762602S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL12039302S1), and TOPMed MESA Multi Omics (HHSN2682015000031/HSN26800004). The MESA projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for the Multi Ethnic Study of Atherosclerosis (MESA) projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01HC95159, 75N92020D00005, N01HC95160, 75N92020D00002, N01HC95161, 75N92020D00003, N01HC95162, 75N92020D00006, N01HC95163, 75N92020D00004, N01HC95164, 75N92020D00007, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, UL1TR000040, UL1TR001079, UL1TR001420, UL1TR001881, DK063491, and R01HL105756. ### 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: IRB of the Medical College of Wisconsin - Milwaukee Campus 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. 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