Loss of the Y chromosome in blood cells and its influence on men health

The Y chromosome is unique to males. As men age, some of their somatic cells lose the Y chromosome during mitosis, creating two distinct cell populations. This phenomenon is known as somatic mosaicism of the Y (mLOY). While mLOY is primarily associated with aging, other factors, such as smoking, heavy drinking, air pollution, and exposure to toxic substances, can exacerbate it. Recent studies have associated mLOY with an increased risk of age-related disorders and reduced life expectancy. This mini-review aims to determine the association between mLOY and diseases in men. A literature search identified 40 articles addressing this issue in men from various populations. This review found an association between mLOY and Alzheimer’s disease, Parkinson’s disease, cardiovascular events, several cancers, hypercholesterolemia, hypertension, diabetes, asthma, lung diseases, kidney disease, rheumatoid arthritis, and an increased susceptibility to respiratory infections, including SARS-CoV-2. Additionally, mLOY was associated with an elevated risk of mortality from various diseases, such as cardiovascular events and chronic kidney disease. The mechanism by which increased mLOY levels in blood cells lead to higher morbidity or mortality is unclear. However, the leading hypothesis suggests that immune dysfunction caused by the dysregulation of several genes on both sex chromosomes and autosomes plays a role. Nevertheless, mLOY-associated risks likely depend on multiple factors, particularly lifestyle. Identifying potential causes of increased mLOY levels is important for developing preventive measures. However, it is unclear to what extent lifestyle changes can impede, delay, or reverse mLOY. Additionally, the clinical usefulness of measuring mLOY has yet to be determined, and its incorporation into routine risk prediction requires validation. Therefore, longitudinal studies are necessary to establish standardized thresholds, as well as the prognostic value and clinical significance of mLOY. These studies must also determine whether detecting mLOY can help identify age-related disorders in men at an earlyb stage.

Men; Y chromosome; Y chromosome somatic mosaicism; mLOY; mLOY-associated disease

[1] Rhie A, Nurk S, Cechova M, Hoyt SJ, Taylor DJ, Altemose N, et al. The complete sequence of a human Y chromosome. Nature. 2023; 621: 344–354.

[2] Dorvall M, Pedersen A, Dumanski JP, Söderholm M, Lindgren AG, Stanne TM, et al. Mosaic loss of chromosome Y is associated with functional outcome after ischemic stroke. Stroke. 2023; 54: 2434–2437.

[3] Noveski P, Madjunkova S, Sukarova Stefanovska E, Matevska Geshkovska N, Kuzmanovska M, Dimovski A, et al. Loss of Y chromosome in peripheral blood of colorectal and prostate cancer patients. PLOS ONE. 2016; 11: e0146264.

[4] Wright DJ, Day FR, Kerrison ND, Zink F, Cardona A, Sulem P, et al. Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. Nature Genetics. 2017; 49: 674–679.

[5] Corchete Sanchez LA, Rheinbay E. Lost but not least: Y chromosome loss as a driver of cancer. Trends in Cancer. 2026; 12: 262–274.

[6] Thompson DJ, Genovese G, Halvardson J, Ulirsch JC, Wright DJ, Terao C, et al.; International Lung Cancer Consortium (INTEGRAL-ILCCO); Breast Cancer Association Consortium; Consortium of Investigators of Modifiers of BRCA1/2; Endometrial Cancer Association Consortium; Ovarian Cancer Association Consortium; Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) Consortium; Kidney Cancer GWAS Meta-Analysis Project; eQTLGen Consortium; Biobank-based Integrative Omics Study (BIOS) Consortium; 23andMe Research Team. Genetic predisposition to mosaic Y chromosome loss in blood. Nature. 2019; 575: 652–657.

[7] Kipling D, Warburton PE. Centromeres, CENP-B and Tigger too. Trends in Genetics. 1997; 13: 141–145.

[8] Lange J, Skaletsky H, van Daalen SK, Embry SL, Korver CM, Brown LG, et al. Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes. Cell. 2009; 138: 855–869.

[9] Miyado M, Fukami M. Losing maleness: somatic Y chromosome loss at every stage of a man’s life. FASEB BioAdvances. 2019; 1: 350–352.

[10] Guo X, Dai X, Zhou T, Wang H, Ni J, Xue J, et al. Mosaic loss of human Y chromosome: what, how and why. Human Genetics. 2020; 139: 421–446.

[11] Dumanski JP, Rasi C, Lönn M, Davies H, Ingelsson M, Giedraitis V, et al. Smoking is associated with mosaic loss of chromosome Y. Science. 2015; 347: 81–83.

[12] Guo X, Dai X. A complex systems approach to mosaic loss of the Y chromosome. GeroScience. 2025; 47: 631–651.

[13] Chang VC, Koutros S, Hurwitz LM, Zhou W, Andreotti G, Parks CG, et al. The association between glyphosate use and mosaic loss of chromosome Y in buccal samples among male pesticide applicators in the Agricultural Health Study. Environment International. 2025; 203: 109755.

[14] Hurwitz LM, Chang VC, Beane Freeman LE, Machiela MJ, Zhou W, Andreotti G, et al. Organochlorine pesticide use and mosaic loss of chromosome Y in a study of male farmers. Environmental Research. 2025; 277: 121539.

[15] Wong JYY, Margolis HG, Machiela M, Zhou W, Odden MC, Psaty BM, et al. Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study. Environment International. 2018; 116: 239–247.

[16] Guan X, Meng X, Zhong G, Zhang Z, Wang C, Xiao Y, et al. Particulate matter pollution, polygenic risk score and mosaic loss of chromosome Y in middle-aged and older men from the Dongfeng-Tongji cohort study. Journal of Hazardous Materials. 2024; 471: 134315.

[17] Liu Y, Bai Y, Wu X, Li G, Wei W, Fu W, et al. Polycyclic aromatic hydrocarbons exposure and their joint effects with age, smoking, and TCL1A variants on mosaic loss of chromosome Y among coke-oven workers. Environmental Pollution. 2020; 258: 113655.

[18] Kobayashi T, Hachiya T, Lu Y, Ikehata Y, China T, Kawano H, et al. Local radiotherapy for cancer patients is associated with mosaic loss of chromosome Y, a hallmark of male aging. npj Aging. 2025; 11: 69.

[19] Lin SH, Loftfield E, Sampson JN, Zhou W, Yeager M, Freedman ND, et al. Mosaic chromosome Y loss is associated with alterations in blood cell counts in UK Biobank men. Scientific Reports. 2020; 10: 3655.

[20] Cheng C, Hong W, Li Y, Xiao X, McKay J, Han Y, et al.; INTEGRAL-ILCCO Lung Cancer Consortium. Mosaic chromosomal alterations are associated with increased lung cancer risk: insight from the INTEGRAL-ILCCO cohort analysis. Journal of Thoracic Oncology. 2023; 18: 1003–1016.

[21] Jakubek YA, Ma X, Stilp AM, Yu F, Bacon J, Wong JW, et al. Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood. The American Journal of Human Genetics. 2025; 112: 276–290.

[22] Sato G, Yamamoto Y, Sonehara K, Saiki R, Ojima T, Kanai M, et al. Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes. Nature Medicine. 2026; 32: 894–905.

[23] Fukami M, Miyado M. Mosaic loss of the Y chromosome and men’s health. Reproductive Medicine and Biology. 2022; 21: e12445.

[24] Dirican CD, Nelson PS. Y chromosome loss and implications for oncology. Molecular Cancer Research. 2024; 22: 603–612.

[25] Sano S, Walsh K. Loss of the Y chromosome in coronary artery disease. European Heart Journal. 2025; 46: 1617–1619.

[26] Loftfield E, Zhou W, Graubard BI, Yeager M, Chanock SJ, Freedman ND, et al. Predictors of mosaic chromosome Y loss and associations with mortality in the UK Biobank. Scientific Reports. 2018; 8: 12316.

[27] Grassmann F, Kiel C, den Hollander AI, Weeks DE, Lotery A, Cipriani V, et al.; International Age-related Macular Degeneration Genomics Consortium (IAMDGC). Y chromosome mosaicism is associated with age-related macular degeneration. European Journal of Human Genetics. 2019; 27: 36–41.

[28] Dumanski JP, Lambert JC, Rasi C, Giedraitis V, Davies H, Grenier-Boley B, et al. Mosaic loss of chromosome Y in blood is associated with Alzheimer disease. American Journal of Human Genetics. 2016; 98: 1208–1219.

[29] García-González P, de Rojas I, Moreno-Grau S, Montrreal L, Puerta R, Alarcón-Martín E, et al. Mendelian randomisation confirms the role of Y-chromosome loss in Alzheimer’s disease aetiopathogenesis in men. International Journal of Molecular Sciences. 2023; 24: 898.

[30] Wang J, Chen X, Du W, Lin C, Liao Y, Corvol JC, et al.; International Genetics of Parkinson Disease Progression (IGPP) Consortium. Impact of Y chromosome loss on the risk of Parkinson’s disease and progression. eBioMedicine. 2025; 117: 105769.

[31] Su WM, Duan QQ, He SY, Liu RY, Wen XJ, Zhang N, et al. Loss of Y chromosome and its implications in male amyotrophic lateral sclerosis: insights from the UK Biobank. BMC Medicine. 2025; 24: 48.

[32] Haitjema S, Kofink D, van Setten J, van der Laan SW, Schoneveld AH, Eales J, et al. Loss of Y chromosome in blood is associated with major cardiovascular events during follow-up in men after carotid endarterectomy. Circulation: Cardiovascular Genetics. 2017; 10: e001544.

[33] Lim J, Hubbard AK, Blechter B, Shi J, Zhou W, Loftfield E, et al. Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom. Journal of the American Heart Association. 2024; 13: e036984.

[34] Zhao C, Huang Y, Ma T, Cheng X, Li J, Zhang G, et al. Association of hematopoietic loss of Y chromosome with valvular heart disease incidence and sex susceptibility. Journal of Advanced Research. 2026; 81: 709–716.

[35] Thel MC, Cochran JD, Teruya S, Hayashi O, Xie CR, Srinivasan AR, et al. Mosaic loss of the Y chromosome is enriched in patients with wild-type transthyretin cardiac amyloidosis and associated with increased mortality. Circulation: Heart Failure. 2024; 17: e011681.

[36] Weng C, Zhao Y, Song M, Shao Z, Pang Y, Yu C, et al.; China Kadoorie Biobank Collaborative Group. Mosaic loss of chromosome Y, tobacco smoking and risk of age-related lung diseases: insights from two prospective cohorts. European Respiratory Journal. 2024; 64: 2400968.

[37] Loftfield E, Zhou W, Yeager M, Chanock SJ, Freedman ND, Machiela MJ. Mosaic Y loss is moderately associated with solid tumor risk. Cancer Research. 2019; 79: 461–466.

[38] Saw WY, Kim K, Huang Y, Yun JH, Ma X, Bacon J, et al.; NHLBI Trans-Omics for Precision Medicine Consortium. Mosaic loss of Y chromosome associates with lung function, emphysema and epigenetic aging. American Journal of Respiratory and Critical Care Medicine. 2026; 212: 1483–1494.

[39] Arai Y, Chavkin NW, Arai Y, Halvardson J, Bjurling J, Doviak H, et al. Hematopoietic loss of Y chromosome activates immune checkpoints and contributes to impaired senescent cell clearance and renal disease. Science Translational Medicine. 2025; 17: eadv4071.

[40] Kimura A, Hishimoto A, Otsuka I, Okazaki S, Boku S, Horai T, et al. Loss of chromosome Y in blood, but not in brain, of suicide completers. PLOS ONE. 2018; 13: e0190667.

[41] Uchiyama S, Ishikawa Y, Ikari K, Honda S, Hikino K, Tanaka E, et al. Mosaic loss of chromosome Y characterises late-onset rheumatoid arthritis and contrasting associations of polygenic risk score based on age at onset. Annals of the Rheumatic Diseases. 2025; 84: 1313–1323.

[42] Zekavat SM, Lin SH, Bick AG, Liu A, Paruchuri K, Wang C, et al. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nature Medicine. 2021; 27: 1012–1024.

[43] Pérez-Jurado LA, Cáceres A, Balagué-Dobón L, Esko T, López de Heredia M, Quintela I, et al.; SCOURGE Cohort Group. Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2. Communications Biology. 2024; 7: 202.

[44] Bruhn-Olszewska B, Davies H, Sarkisyan D, Juhas U, Rychlicka-Buniowska E, Wójcik M, et al. Loss of Y in leukocytes as a risk factor for critical COVID-19 in men. Genome Medicine. 2022; 14: 139.

[45] Machiela MJ, Dagnall CL, Pathak A, Loud JT, Chanock SJ, Greene MH, et al. Mosaic chromosome Y loss and testicular germ cell tumor risk. Journal of Human Genetics. 2017; 62: 637–640.

[46] Petzinna SM, Kirch SM, Adamson MS, Xi D, Bauer CJ, Kreis L, et al. AYLo study—elevated relapse risk and dysregulated proinflammatory signaling in giant cell arteritis patients with mosaic loss of the Y chromosome. Annals of the Rheumatic Diseases. 2025; 84: 1900–1908.

[47] Qin N, Li N, Wang C, Pu Z, Ma Z, Jin G, et al. Association of mosaic loss of chromosome Y with lung cancer risk and prognosis in a Chinese population. Journal of Thoracic Oncology. 2019; 14: 37–44.

[48] Espinosa M, Herrera I, Buendía-Roldán I, Meléndez-Zajgla J, Pardo A, Selman M. Determination of loss of chromosome Y in peripheral blood cells in males with idiopathic pulmonary fibrosis. European Respiratory Journal. 2024; 64: 2401303.

[49] Jiang L, Song M, Song F, Zhou Y, Yao H, Li G, et al. Characterization of loss of chromosome Y in peripheral blood cells in male Han Chinese patients with schizophrenia. BMC Psychiatry. 2023; 23: 469.

[50] Lin SH, Brown DW, Rose B, Day F, Lee OW, Khan SM, et al. Incident disease associations with mosaic chromosomal alterations on autosomes, X and Y chromosomes: insights from a phenome-wide association study in the UK Biobank. Cell & Bioscience. 2021; 11: 143.

[51] Hozakowska-Roszkowska DM, Mengel-From J, Hristozova TK, Pedersen JK, Jeune B, Andersen-Ranberg K, et al. Mosaic loss of Y chromosome and the association to mortality in Danish men aged 56–100 years. Mechanisms of Ageing and Development. 2024; 222: 111979.

[52] Weyrich M, Cremer S, Gerster M, Sarakpi T, Rasper T, Zewinger S, et al. Loss of Y chromosome and cardiovascular events in chronic kidney disease. Circulation. 2024; 150: 746–757.

[53] Bjurling J, Chavkin NW, Halvardson J, Thel MC, Mattisson J, Kim JS, et al. Mosaic loss of chromosome Y in blood is associated with male susceptibility for idiopathic pulmonary fibrosis. Communications Medicine. 2025; 5: 246.

[54] Weyrich M, Zewinger S, Sarakpi T, Rasper T, Kleber ME, Cremer S, et al. Mosaic loss of Y chromosome and mortality after coronary angiography. European Heart Journal. 2025; 46: 1603–1616.

[55] Mas-Peiro S, Abplanalp WT, Rasper T, Berkowitsch A, Leistner DM, Dimmeler S, et al. Mosaic loss of Y chromosome in monocytes is associated with lower survival after transcatheter aortic valve replacement. European Heart Journal. 2023; 44: 1943–1952.

[56] Cremer S, von Scheidt M, Kirschbaum K, Tombor L, Mas-Peiro S, Abplanalp W, et al. Prognostic significance of somatic mutations in myeloid cells of men with chronic heart failure—interaction between loss of Y chromosome and clonal haematopoiesis. European Journal of Heart Failure. 2025; 27: 3219–3234.

[57] Li N, Li J, Tan Y, Chen R, Zhao X, Zhou P, et al. Age-related loss of Y chromosome is associated with mortality after ST-segment elevation myocardial infarction. Communications Medicine. 2026; 6: 476.

[58] Dumanski JP, Halvardson J, Davies H, Rychlicka-Buniowska E, Mattisson J, Moghadam BT, et al. Immune cells lacking Y chromosome show dysregulation of autosomal gene expression. Cellular and Molecular Life Sciences. 2021; 78: 4019–4033.

[59] Dawoud A, Green L, Rackham O. Loss of chromosome Y associates with altered immune cell trajectories and X-inactivation features. Aging Cell. 2026; 25: e70528.

[60] Mattisson J, Halvardson J, Davies H, Bruhn-Olszewska B, Olszewski P, Danielsson M, et al. Loss of chromosome Y in regulatory T cells. BMC Genomics. 2024; 25: 243.

[61] Wójcik M, Juhas U, Mohammadi E, Mattisson J, Drężek-Chyła K, Rychlicka-Buniowska E, et al. Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases. Scientific Reports. 2024; 14: 9458.

[62] Abdel-Hafiz HA, Schafer JM, Chen X, Xiao T, Gauntner TD, Li Z, et al. Y chromosome loss in cancer drives growth by evasion of adaptive immunity. Nature. 2023; 619: 624–631.

[63] Wang Y, Sano S. Why Y matters? The implication of loss of Y chromosome in blood and cancer. Cancer Science. 2024; 115: 706–714.

[64] Chen X, Shen Y, Choi S, Abdel-Hafiz HA, Basu M, Hoelzen L, et al. Concurrent loss of the Y chromosome in cancer and T cells impacts outcome. Nature. 2025; 642: 1041–1050.

[65] Vermeulen MC, Pearse R, Young-Pearse T, Mostafavi S. Mosaic loss of chromosome Y in aged human microglia. Genome Research. 2022; 32: 1795–1807.

[66] Jąkalski M, Bruhn-Olszewska B, Rychlicka-Buniowska E, Davies H, Sarkisyan D, Siedlar M, et al. DNA methylation patterns contribute to changes of cellular differentiation pathways in leukocytes with LOY from patients with Alzheimer’s disease. Cellular and Molecular Life Sciences. 2025; 82: 93.

[67] Wilson PC, Verma A, Yoshimura Y, Muto Y, Li H, Malvin NP, et al. Mosaic loss of Y chromosome is associated with aging and epithelial injury in chronic kidney disease. Genome Biology. 2024; 25: 36.

[68] Dawoud AAZ, Tapper WJ, Cross NCP. Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations. Science Advances. 2023; 9: eade9746.

[69] Hubbard AK, Brown DW, Zhou W, Lin SH, Genovese G, Chanock SJ, et al. Serum biomarkers are altered in UK Biobank participants with mosaic chromosomal alterations. Human Molecular Genetics. 2023; 32: 3146–3152.

[70] Weyrich M, Windschmitt J, Abplanalp WT, Ware A, Sarakpi T, Zewinger S, et al. Loss of Y chromosome: proteomic signatures in human cardiovascular disease. European Heart Journal. 2025; 46: 5237–5239.

[71] Riaz M, Mattisson J, Polekhina G, Bakshi A, Halvardson J, Danielsson M, et al. A polygenic risk score predicts mosaic loss of chromosome Y in circulating blood cells. Cell & Bioscience. 2021; 11: 205.