Novel genetic determinants of telomere length from a trans-ethnic analysis of 109,122 whole genome sequences in TOPMed

ABSTRACT Telomeres shorten in replicating somatic cells, and telomere length (TL) is associated with age-related diseases 1,2 . To date, 17 genome-wide association studies (GWAS) have identified 25 loci for leukocyte TL 3–19 , but were limited to European and Asian ancestry individuals and relied on laboratory assays of TL. In this study from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of TL in n=109,122 trans-ethnic (European, African, Asian and Hispanic/Latino) individuals. We identified 59 sentinel variants (p-value <5×10 −9 ) from 36 loci (20 novel, 13 replicated in external datasets). There was little evidence of effect heterogeneity across populations, and 10 loci had >1 independent signal. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 ( STN1 ). We further identified two novel genes, DCLRE1B ( SNM1B ) and PARN , using a multi-variant gene-based approach.