Faculty Collaboration Database

Mosaic loss of Y chromosome associates with lung function, emphysema, and epigenetic aging. Am J Respir Crit Care Med 2026 Jul 01;212(7):1483-1494

Date

05/05/2026

Pubmed ID

42085243

Pubmed Central ID

PMC13322295

DOI

10.1093/ajrccm/aamag120

Scopus ID

2-s2.0-105043543172 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

RATIONALE: As the global population ages, identifying risk factors for age-related diseases, such as COPD, is crucial for public health. Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mosaicism event, but its relationship with pulmonary health remains undercharacterized.

OBJECTIVES: To examine the association between mLOY and pulmonary outcomes in men.

METHODS: Leveraging mLOY assessment (cell fraction ≥ 5%) in over 12 000 men, including 5097 from the COPDGene Study and 7235 from six additional cohorts in the Trans-Omics for Precision Medicine program, we investigated mLOY associations with respiratory outcomes and epigenetic aging using multivariable cross-sectional, longitudinal, and prospective models. Primary outcomes included spirometry, CT-based emphysema, and epigenetic pace of aging.

RESULTS: The prevalence of mLOY increased with age. Cross-sectionally, mLOY was associated with airflow obstruction, with reduced FEV1/FVC of 0.018 [95% CI, -0.030 to -0.006] in COPDGene and 0.020 [95% CI, -0.027 to -0.013] in TOPMed. mLOY was also associated with greater CT-quantified lung emphysema and faster pace epigenetic aging. Longitudinally, mLOY was associated with faster FEV1 decline (∼55mL/year vs ∼38mL/year). Prospectively, mLOY was associated with higher odds of developing COPD [OR = 1.84, 95% CI, 1.10-3.07] and preserved ratio impaired spirometry (PRISm) [OR = 2.87, 95% CI, 1.09-7.56] among participants with normal lung function at baseline. Associations remained robust after adjusting for clonal hematopoiesis and telomere length.

CONCLUSIONS: mLOY is associated with lower lung function, accelerated lung function decline, higher emphysema, and faster pace of aging, positioning mLOY as a potential biomarker of respiratory aging in men.

Author List

Saw WY, Kim K, Huang Y, Yun JH, Ma X, Bacon J, Pershad Y, Levy D, O'Connor GT, Boerwinkle E, Barr RG, Rich SS, Rotter JI, Carson AP, Raffield LM, Gharib SA, Bartz TM, Psaty BM, Sofer T, North KE, Kaplan RC, Oelsner EC, Manichaikul A, Bick AG, Scheet P, Reiner AP, NHLBI Trans-Omics for Precision Medicine Consortium, Jakubek YA, Auer PL, Cho MH, DeMeo DL

Authors

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Aging
Chromosomes, Human, Y
Cross-Sectional Studies
Epigenesis, Genetic
Humans
Male
Middle Aged
Mosaicism
Prospective Studies
Pulmonary Disease, Chronic Obstructive
Pulmonary Emphysema
Respiratory Function Tests
Spirometry