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

Yasminka A Jakubek¹, Xiaolong Ma², Adrienne M Stilp³, Fulong Yu⁴, Jason Bacon⁵, Justin W Wong⁶, Francois Aguet⁷, Kristin Ardlie⁷, Donna K Arnett⁸, Kathleen Barnes⁹, Joshua C Bis¹⁰, Tom Blackwell¹¹, Lewis C Becker¹², Eric Boerwinkle¹³, Russell P Bowler¹⁴, Matthew J Budoff¹⁵, April P Carson¹⁶, Jiawen Chen¹⁷, Michael H Cho¹⁸, Josef Coresh¹⁹, Nancy J Cox²⁰, Paul S de Vries¹³, Dawn L DeMeo¹⁸, David W Fardo²¹, Myriam Fornage²², Xiuqing Guo²³, Michael E Hall¹⁶, Nancy Heard-Costa²⁴, Bertha Hidalgo²⁵, Marguerite Ryan Irvin²⁵, Andrew D Johnson²⁶, Eric Jorgenson²⁷, Eimear E Kenny²⁸, Michael D Kessler²⁷, Daniel Levy²⁶, Yun Li²⁹, Joao A C Lima¹², Yongmei Liu³⁰, Adam E Locke²⁷, Ruth J F Loos³¹, Mitchell J Machiela³², Rasika A Mathias³³, Braxton D Mitchell³⁴, Joanne M Murabito³⁵, Josyf C Mychaleckyj³⁶, Kari E North³⁷, Peter Orchard³⁸, Stephen C J Parker³⁹, Yash Pershad²⁰, Patricia A Peyser⁴⁰, Katherine A Pratte⁴¹, Bruce M Psaty⁴², Laura M Raffield⁴³, Susan Redline⁴⁴; Regeneron Genetics Center; Stephen S Rich³⁶, Jerome I Rotter²³, Sanjiv J Shah⁴⁵, Jennifer A Smith⁴⁶, Aaron P Smith⁴⁷, Albert Smith¹¹, Margaret A Taub⁴⁸, Hemant K Tiwari⁴⁹, Russell Tracy⁵⁰, Bjoernar Tuftin⁴³; NHLBI Trans-Omics for Precision Medicine Consortium; Alexander G Bick²⁰, Vijay G Sankaran⁵¹, Alexander P Reiner⁵², Paul Scheet⁶, Paul L Auer⁵³

Affiliations

¹ Department of Internal Medicine, University of Kentucky, Lexington, KY, USA.
² Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
³ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁴ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China.
⁵ Department of Computer Science, Department of Biological Sciences, University of Wisconsin Milwaukee, Milwaukee, WI, USA.
⁶ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Broad Institute, Cambridge, MA, USA.
⁸ University of South Carolina, Columbia, SC, USA.
⁹ Division of Biomedical Informatics and Personalized Medicine, School of Medicine, School of Medicine University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
¹⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Medicine, Division of Cardiology, Johns Hopkins Hospital, Johns Hopkins University of Medicine, Baltimore, MD, USA.
¹³ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁴ Department of Medicine, National Jewish Health, Denver, CO, USA.
¹⁵ Department of Medicine, Division of Cardiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁶ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁷ Department of Biostatistics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
¹⁸ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA.
²⁰ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
²¹ Department of Biostatistics, University of Kentucky, Lexington, KY, USA.
²² University of Texas Health Science Center at Houston, Houston, TX, USA.
²³ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁴ Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
²⁵ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁶ Framingham Heart Study, Framingham, MA, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
²⁷ Regeneron Genetics Center, Tarrytown, NY, USA.
²⁸ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁹ Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
³⁰ Duke University School of Medicine, Durham, NC, USA.
³¹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³² Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
³³ Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁴ Department of Medicine, University of Maryland Baltimore, Baltimore, MD, USA.
³⁵ Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
³⁶ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
³⁷ Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
³⁸ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
³⁹ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
⁴⁰ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁴¹ Department of Biostatistics, National Jewish Health, Denver, CO, USA.
⁴² Cardiovascular Health Research Unit, Department of Medicine, Department of Epidemiology, Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴³ Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
⁴⁴ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴⁵ Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA; Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, MI, USA.
⁴⁷ Institute for Biomedical Informatics, University of Kentucky, Lexington, KY, USA.
⁴⁸ Department of Biostatistics, Johns Hopkins University, Baltimore, MD, USA.
⁴⁹ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁵⁰ Departments of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA.
⁵¹ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA.
⁵² Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵³ Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: pauer@mcw.edu.

PMID: 39809269
PMCID: PMC11866972
DOI: 10.1016/j.ajhg.2024.12.014

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

Yasminka A Jakubek et al. Am J Hum Genet. 2025.

. 2025 Feb 6;112(2):276-290.

doi: 10.1016/j.ajhg.2024.12.014. Epub 2025 Jan 13.

Authors

Affiliations

¹ Department of Internal Medicine, University of Kentucky, Lexington, KY, USA.
² Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
³ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁴ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China.
⁵ Department of Computer Science, Department of Biological Sciences, University of Wisconsin Milwaukee, Milwaukee, WI, USA.
⁶ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Broad Institute, Cambridge, MA, USA.
⁸ University of South Carolina, Columbia, SC, USA.
⁹ Division of Biomedical Informatics and Personalized Medicine, School of Medicine, School of Medicine University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
¹⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Medicine, Division of Cardiology, Johns Hopkins Hospital, Johns Hopkins University of Medicine, Baltimore, MD, USA.
¹³ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁴ Department of Medicine, National Jewish Health, Denver, CO, USA.
¹⁵ Department of Medicine, Division of Cardiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁶ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁷ Department of Biostatistics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
¹⁸ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA.
²⁰ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
²¹ Department of Biostatistics, University of Kentucky, Lexington, KY, USA.
²² University of Texas Health Science Center at Houston, Houston, TX, USA.
²³ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁴ Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
²⁵ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁶ Framingham Heart Study, Framingham, MA, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
²⁷ Regeneron Genetics Center, Tarrytown, NY, USA.
²⁸ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁹ Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
³⁰ Duke University School of Medicine, Durham, NC, USA.
³¹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³² Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
³³ Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁴ Department of Medicine, University of Maryland Baltimore, Baltimore, MD, USA.
³⁵ Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
³⁶ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
³⁷ Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
³⁸ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
³⁹ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
⁴⁰ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁴¹ Department of Biostatistics, National Jewish Health, Denver, CO, USA.
⁴² Cardiovascular Health Research Unit, Department of Medicine, Department of Epidemiology, Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴³ Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
⁴⁴ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴⁵ Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA; Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, MI, USA.
⁴⁷ Institute for Biomedical Informatics, University of Kentucky, Lexington, KY, USA.
⁴⁸ Department of Biostatistics, Johns Hopkins University, Baltimore, MD, USA.
⁴⁹ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁵⁰ Departments of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA.
⁵¹ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA.
⁵² Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵³ Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: pauer@mcw.edu.

PMID: 39809269
PMCID: PMC11866972
DOI: 10.1016/j.ajhg.2024.12.014

Abstract

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 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 (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. 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 (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.

Keywords: GWAS; mosaic loss of chromosome Y; multi-ancestry.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests L.M.R. and S.S.R. are consultants 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. E.J., M.D.K., and A.E.L. are current employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals.

Figures

**Figure 1**
mLOY calling pipeline and distribution across age, ancestry, and clonal fraction (A) Overview of data processing for detection of mosaic loss of chromosome Y (mLOY). (B) Fraction of samples (y axis) with mLOY by age (years) bins (x axis). (C) Histogram of the count of samples (y axis) and the estimated fraction of cells in the samples with mLOY (x axis). (D) mLOY odds ratio and 95% confidence interval (adjusted for covariates) for AA, HA, and EAS groups compared to the EUR group.

**Figure 2**
Relative expression of *CFHR1* and *LRP6* Normalized expression of (A) *CFHR1* and (B) *LRP6* across primary human hematopoietic cell types. Counts per million (CPM) is the read count for each gene in each cell divided by the library size of each cell in millions.

**Figure 3**
SCAVENGE analysis of the mLOY trait using a hematopoietic scATAC-seq dataset (A) The uniform manifold approximation and projection (UMAP) plot depicting cell type annotations of scATAC-seq dataset. (B) The UMAP of hematopoietic stem cells (HSCs) labeled as “enriched” or “depleted,” respectively, representing their relevance or non-relevance to mLOY risk by using the permutation tests coupled with SCAVENGE analysis (see material and methods for details). (C) Differential comparison of chromVAR TF motif enrichment between mLOY risk-variant-enriched and variant-depleted HSCs. Bonferroni-adjusted p value is indicated (y axis), and the TFs are ranked accordingly (x axis). The selected TF motifs with the top 10 ranks in each direction are labeled. (D and E) The chromVAR enrichment Z scores for CEBPA and GATA1 motifs are shown in UMAP plots (right) and violin plots (left) across HSCs as shown in (B). (A) presents the UMAP plot for cells of the entire hematopoiesis, including HSCs, progenitor cells, and various terminal cells. Since our focus is on the heterogeneity of LOY association in HSCs, we extracted all the HSCs from the dataset in (A) for the SCAVENGE analysis. The same x and y coordinates are used in (A) and (E). The spread of cell distribution shown in (B) and (E) results from displaying all the HSCs in one panel, which represents only a subset of the cells in (A).

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Update of

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.
Jakubek YA, Ma X, Stilp AM, Yu F, Bacon J, Wong JW, Aguet F, Ardlie K, Arnett D, Barnes K, Bis JC, Blackwell T, Becker LC, Boerwinkle E, Bowler RP, Budoff MJ, Carson AP, Chen J, Cho MH, Coresh J, Cox N, de Vries PS, DeMeo DL, Fardo DW, Fornage M, Guo X, Hall ME, Heard-Costa N, Hidalgo B, Irvin MR, Johnson AD, Kenny EE, Levy D, Li Y, Lima JA, Liu Y, Loos RJF, Machiela MJ, Mathias RA, Mitchell BD, Murabito J, Mychaleckyj JC, North K, Orchard P, Parker SC, Pershad Y, Peyser PA, Pratte KA, Psaty BM, Raffield LM, Redline S, Rich SS, Rotter JI, Shah SJ, Smith JA, Smith AP, Smith A, Taub M, Tiwari HK, Tracy R, Tuftin B, Bick AG, Sankaran VG, Reiner AP, Scheet P, Auer PL. Jakubek YA, et al. medRxiv [Preprint]. 2024 Apr 19:2024.04.16.24305851. doi: 10.1101/2024.04.16.24305851. medRxiv. 2024. Update in: Am J Hum Genet. 2025 Feb 06;112(2):276-290. doi: 10.1016/j.ajhg.2024.12.014. PMID: 38699360 Free PMC article. Updated. Preprint.

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources