A polygenic risk score predicts mosaic loss of chromosome Y in circulating blood cells

Abstract

Background Mosaic loss of Y chromosome (LOY) is the most common somatic change that occurs in circulating white blood cells of older men. LOY in leukocytes is associated with increased risk for all-cause mortality and a range of common disease such as hematological and non-hematological cancer, Alzheimer’s disease, and cardiovascular events. Recent genome-wide association studies identified up to 156 germline variants associated with risk of LOY. The objective of this study was to use these variants to calculate a novel polygenic risk score (PRS) for LOY, and to assess the predictive performance of this score in a large independent population of older men. Results We calculated a PRS for LOY in 5131 men aged 70 years and older. Levels of LOY were estimated using microarrays and validated by whole genome sequencing. After adjusting for covariates, the PRS was a significant predictor of LOY (odds ratio [OR] = 1.74 per standard deviation of the PRS, 95% confidence intervals [CI] 1.62–1.86, p < 0.001). Men in the highest quintile of the PRS distribution had > fivefold higher risk of LOY than the lowest (OR = 5.05, 95% CI 4.05–6.32, p < 0.001). Adding the PRS to a LOY prediction model comprised of age, smoking and alcohol consumption significantly improved prediction (AUC = 0.628 [CI 0.61–0.64] to 0.695 [CI 0.67–0.71], p < 0.001). Conclusions Our results suggest that a PRS for LOY could become a useful tool for risk prediction and targeted intervention for common disease in men.

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

“…Of note, mloy-PRS successfully predicted mLOY events in our data and was not associated with age or APOE genotype ( Figure S4 and Table S5 ). A recently published work found similar effect sizes of this PRS for predicting mLOY calls [ 33 ]. Therefore, analysis of mloy-PRS instead of mLOY phenotypes allowed us to overcome the main limitations of the study (age differences and sample size) by providing an age-independent mLOY instrument.…”

Why do we age? The main signs of aging

“…Дослідники також повідомляють, що коли Y-хромосому видаляли у мишей-самців, то тварини гинули раніше, ніж її носії, можливо, через те, що їхня серцева тканина ставала фіброзною та втрачала еластичність [46,47]. На думку генетиків, це найкращий доказ того, що втрата Y-хромосоми шкодить здоров'ю.…”