Telomere length (TL) is considered a molecular/cellular hallmark of aging. Fifteen recent genome-wide association studies (GWAS) have found 16 TL loci. These prior GWAS have two limitations: (i) almost all have been in European ancestry individuals; and (ii) all have relied on array genotype data. Therefore, very little is known about the specific causal variants, and even less about the genetic architecture of these loci in individuals with other ancestral backgrounds.

We leverage TOPMed whole-genome sequencing (WGS) data to estimate TL bioinformatically using TelSeq software in the largest multi-ethnic dataset for TL GWAS to date. Genomewide tests for association in a meta-analysis of n=46,458 discovery and n=28,718 replication samples were performed using GENESIS on 82M variants with minor allele count >= 5, adjusting for age, sex, study, sequencing center, population structure and relatedness. We identified 22 loci (p <5x10-8), including 9 prior and 13 novel loci. Several of the novel loci map to genes that play a role in telomere biology: RFWD3, TERF1, TINF2, POT1, ATM, SAMHD1, and TERF2. Of the top 25 pathways identified in gene set enrichment analysis for these loci (FDR< 5.6x10-5), 24 are related to telomere length/maintenance, DNA regulation, telomere capping/loop disassembly, and telomere organization.

We estimate TL heritability to be 47%, consistent with previous reports. Stratified analysis was performed by race/ethnicity: African (n=21179), Asian (n=4754), Hispanic/Latino (n=9808), European (n=38193), and Samoan (n=1242), and several loci show population differences. In particular, TINF2 has a strong association in the Samoan (alternate allele frequency (AAF)=0.23; p=1.3x10-7), Asian (AAF=0.09; p=1.3x10-5) and African (AAF=0.01; p=2.6x10-4) groups, and no association in the European group (AAF <0.005). PheWAS of sentinel variants at TERT and TERC had associations with myeloproliferative neoplasms, cancers of skin/brain, and leiomyoma/benign neoplasms of the uterus (all p<10-8) in the UK Biobank. Sentinel variants at NAF1, TERF1, ZNF729, POT1, and CHKB-AS1 had suggestive associations with uterine fibroids (p=0.008 to 0.07).

We showcase the promise of leveraging WGS in TOPMed for TL genetics in the context of race and ancestry. Future efforts include fine-mapping and co-localization analysis using GTEx and eQTLGen whole blood eQTLs to identify functional variants, with an emphasis on loci showing population differences in signal.