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 backgrounds across the United States. 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 United States, accounting for age, sex, and genetic ancestry. Genome-wide association study and meta-analysis with the UK Biobank (n=679,972) found 234 non-overlapping loci, of which 36 were novel. We identified 4 novel loci unique to non-European-like populations and one specific to females. Rare variant analysis uncovered 7 novel genes, providing new functional insights. Our study highlighted previously underappreciated contextual heterogeneities of phenomic and genomic associations with LTL.