Genomic, phenomic and geographic associations of leukocyte telomere length in the United States

Leukocyte telomere length (LTL) is associated with multiple conditions, including cardiovascular diseases and neoplasms, yet their differential associations across diverse individuals are largely unknown. We estimated LTL from blood-derived whole-genome sequences in the All of Us research program (n = 242,494) with diverse ancestries across the USA. LTL was associated with lifestyle, socioeconomic status, biomarkers, cardiometabolic diseases and neoplasms, with heterogeneity across genetic ancestries and sexes. Geographical analysis revealed that significantly longer LTL clustered in the West Coast and Central Midwest, while significantly shorter LTL clustered in the Southeast in the USA. Genome-wide association studies and meta-analyses with the UK Biobank (n = 679,972) found 234 nonoverlapping loci, of which 37 were novel. We identified six novel loci unique to non-European-like populations and one specific to women. Rare variant analysis uncovered nine novel genes, providing new functional insights. Our study highlighted underappreciated contextual heterogeneities of phenomic and genomic associations with LTL.