Telomere length (TL) is a proposed biomarker of biological age and is a risk factor for age-related diseases. Prior GWAS have identified numerous loci harboring genetic determinants of TL; several of these being implicated in human disease. However, studies have been limited to samples of European and Asian ancestry. We performed a GWAS of TL with 1,261 participants of Samoan ancestry. Whole-genome sequencing was conducted by the TOPMed Program, and TelSeq was used to compute TL from the sequences. We tested for association via linear mixed models as implemented in GENESIS, with age and sex as fixed effect covariates. We adjusted for relatedness and population stratification with values from PC-AiR and PC-Relate, respectively. There was one signal associated with TL at p<5×10⁻⁸ and two additional signals associated with TL at p<1×10⁻⁶. The peak variant is located on 14q12. This top signal (p=2.7×10⁻8) was rs4982872, an intronic variant in NEDD8, with the minor allele (MAF=0.26) associated with greater mean TL (0.12bp). This variant is in high LD (r²=1) with rs28372734, which is located in the 5′-UTR of TINF2, a gene that encodes for a member protein of the telosome/shelterin complex. Given that TINF2 has been reported to be associated with TL in people of Asian ancestry, we conditioned on rs28372734, to determine if there is more than one locus mapping to this region in our study. The association with rs4982872 is lost, suggesting that the peak variant (rs4982872) here, also maps to the previously reported TINF2 locus. Importantly, the MAF of the variants mapping to the TINF2 locus is quite different between Samoans and populations of continental ancestries. The MAF of rs28372734 is 23% in Samoans and is 9% in individuals of Asian ancestries but is ≤ 1% in individuals of African and European ancestries; in fact, TINF2 is completely missed in prior GWAS focused on European ancestries. Additionally, we observed novel association at p<1×10⁻6 of two variants in intergenic regions near PTPRG and AC005562.1 located on chromosomes 3 and 17, respectively. The minor alleles for both variants are rare in the Samoans (MAF= 0.006 and 0.008, respectively) and are not observed in populations of continental ancestries. These variants have not been reported to be associated with TL in any studies to date. Among participants of Samoan ancestry, we see the prior association with a high MAF variant in the TINF2 locus and identify two novel associations associated with TL. Additional work is necessary to replicate these novel associations and understand the biological mechanisms that may explain differences in TL associated with these variants.

Telomere length (TL) regulation is critical for human health. Individuals with very short TL exhibit Short Telomere Syndromes (STS) leading to organ failure, while individuals with very long TL may be predisposed to cancer. Genome-wide association studies (GWAS) have yielded several TL-associated loci, but the mechanisms underlying most of these signals remains poorly characterized. TL is reported to differ between ancestry groups, yet the majority of previous TL GWAS were limited to European individuals. We recently estimated TL from whole genome sequencing (WGS) bioinformatically using TelSeq in a pooled trans-ethnic study (N=109,122) from the Trans-Omics for Precision Medicine (TOPMed) Program. GWAS using TOPMed data yielded 59 independent, genome-wide significant signals at 36 loci, 21 of which were novel signals. To extend these discoveries beyond TOPMed, we performed a meta-analysis including three additional GWAS from European (1), Singaporean Chinese (2), and South Asian (3) ancestries and the TOPMed data stratified by descent (European, African, Hispanic/Latino, Asian, Brazilian and Samoan) and identified an additional 18 novel loci for a total of 54 GWAS loci. The genes closest to the GWAS and meta-analysis signals were enriched for gene ontology terms involving telomere biology, DNA repair, and DNA metabolism. To understand the mechanisms underlying these signals we performed credible set analysis, colocalization analysis, and functional characterization of all signals. These fine-mapping approaches identified several zinc-finger nucleases and transcription factors (TF) as likely causal genes. ZCCHC8 is a zinc-finger protein and rare variants in ZCCHC8 are reported to cause STS; BANP is a TF which contributes to T cell development and STS patients are reported to have T-cell immunodeficiency. The diversity in our dataset made it possible to identify population-specific signals driven by differences in allele frequency, which included signals near OBFC1, a telomere binding protein. Colocalization analysis with expression quantitative trait loci (eQTLs) from GTEx tissues demonstrated that all signals near OBFC1 colocalize with OBFC1 eQTLs. Notably, the primary OBFC1 signal was driven by European, African, and Hispanic/Latino individuals while an independent, secondary signal was driven exclusively by Asian and Hispanic/Latino individuals. Our results demonstrate the value of including diverse ancestries in GWAS and of WGS in the identification of ancestry-specific and low frequency signals to better understand genetic variation underlying TL regulation.
1. PMC7058826
2. PMC6554354
3. PMC5749304