Novel genetic determinants of telomere length from a multi-ethnic analysis of 75,000 whole genome sequences in TOPMed

Taub, M. A.; Weinstock, J. S.; Iyer, K. R.; Yanek, L. R.; Conomos, M. P.; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,; Reiner, A. P.; Mathias, R. A.

doi:10.1101/749010

bioRxiv · 10.1101/749010

Novel genetic determinants of telomere length from a multi-ethnic analysis of 75,000 whole genome sequences in TOPMed

Taub, M. A.·Weinstock, J. S.·Iyer, K. R.·Yanek, L. R.·Conomos, M. P.·NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,·Reiner, A. P.·Mathias, R. A.

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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 <5x10-9) 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.

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Taub, M. A., Weinstock, J. S., Iyer, K. R., Yanek, L. R., Conomos, M. P., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,, Reiner, A. P., Mathias, R. A.. 2019-09-04. Novel genetic determinants of telomere length from a multi-ethnic analysis of 75,000 whole genome sequences in TOPMed. https://doi.org/10.1101/749010

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