Association Between Mosaic Loss of Y Chromosome and Atrial Fibrillation

Mosaic loss of the Y chromosome (mLoY) is the most common age-related somatic mutation in male humans and has been associated with increased mortality and fibrotic cardiovascular phenotypes.

This study aimed to evaluate the associations among mLoY, atrial fibrillation (AF), and mortality in a large hospital-based biobank cohort.

We analyzed 17,916 male participants aged ≥20 years from the Mass General Brigham Biobank with available genomic and clinical data. mLoY was quantified using mean log R ratio of the Y chromosome values derived from genotyping array data. Two classification approaches were used: histogram-based cutoffs and a mean log R ratio of the Y chromosome-based threshold method. Associations among mLoY, AF, and mortality were evaluated using multivariable logistic regression, adjusting for cardiovascular comorbidities.

Among 2,940 AF patients and 14,976 control participants, mLoY prevalence was higher in AF patients across both classification methods. After adjusting for age and comorbidities, individuals with Y chromosome value <-0.1 had a 25% increased odds of AF (adjusted OR: 1.25; 95% CI: 1.01-1.55). Among patients with AF, mLoY was independently associated with a 37% higher risk of all-cause mortality (adjusted OR: 1.37; 95% CI: 1.06-1.79).

mLoY is independently associated with a higher prevalence of AF and higher mortality among AF patients. These findings support mLoY as a potential biomarker for cardiovascular risk stratification in aging men and highlight fibrosis as a key mechanistic pathway warranting further investigation.