Determinants of chromosome-specific telomere lengths among 2573 All of Us participants

Telomere length is a biomarker of aging and disease risk. Most human studies have assessed average telomere length, limiting our understanding of variability across chromosome arms. Using long-read sequencing data from >2500 All of Us participants, we estimate chromosome-specific telomere lengths and characterize sources of biological and technical variation. Telomere length varies by chromosome arm, accounting for 9.1% of total variance. Substantial variance (8.9%) in chromosome-specific telomere lengths is attributable to individual, independent of age, suggesting that inter-individual differences in length are established at birth and maintained through life. Age is inversely associated with length for all arms, but longer arms show stronger association. We demonstrate that chromosome-specific telomere estimates enable analysis of disease associations for individual telomeres and for individuals' shortest telomere. Overall, this work highlights the utility of long-read sequencing for population-scale analysis of chromosome-specific telomere lengths and provides a framework to guide future studies.