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The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans

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Abstract

Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h2): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., “direct” inheritance). Prior studies of LTL h2 have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5069 Bangladeshi adults with substantial relatedness. For each of the 6318 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (Tshared). We then estimated the association between Tshared and the squared pairwise difference in LTL ((ΔLTL)2) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (ϕ). The association between Tshared and (ΔLTL)2 was inverse among all relative pair types. In a meta-analysis including all relative pairs (ϕ > 0.05), the association between Tshared and (ΔLTL)2 (P = 0.01) was stronger than the association between ϕ and (ΔLTL)2 (P = 0.43). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h2 despite telomere “reprogramming” during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h2 attributable to direct transmission of telomeres.

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Acknowledgements

This work was supported by the National Institutes of Health (R01 ES020506, U01 HG007601, P42 ES10349, R01 CA107431, R01 CA102484, P30 CA014599). The authors thank all the men and women who participated in HEALS and BEST and all research staff who contributed to data collection. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

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  1. Shantanu Roy

    Present address: Division of Foodborne, Waterborne, and Environmental Diseases, Center for Disease Control, Atlanta, GA, 30333, USA

Authors and Affiliations

  1. Department of Public Health Sciences, University of Chicago, Chicago, IL, 60615, USA

    Dayana A. Delgado, Chenan Zhang, Kevin Gleason, Kathryn Demanelis, Lin S. Chen, Shantanu Roy, Justin Shinkle, Mekala Sabarinathan, Lin Tong, Farzana Jasmine, Muhammad G. Kibriya, Habibul Ahsan & Brandon L. Pierce

  2. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA

    Chenan Zhang

  3. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA

    Jianjun Gao

  4. Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, 60637, USA

    Maria Argos

  5. UChicago Research Bangladesh, Dhaka, Bangladesh

    Alauddin Ahmed, Tariqul Islam, Muhammad Rakibuz-Zaman, Golam Sarwar & Hasan Shahriar

  6. Research and Evaluation Division, BRAC, Dhaka, Bangladesh

    Mahfuzar Rahman

  7. International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh

    Muhammad Yunus

  8. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA

    Jennifer A. Doherty

  9. Department of Human Genetics, University of Chicago, Chicago, IL, 60615, USA

    Habibul Ahsan & Brandon L. Pierce

  10. Comprehensive Cancer Center, University of Chicago, Chicago, IL, 60615, USA

    Habibul Ahsan & Brandon L. Pierce

  11. Department of Medicine, University of Chicago, Chicago, IL, 60615, USA

    Habibul Ahsan

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  1. Dayana A. Delgado
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  2. Chenan Zhang
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  3. Kevin Gleason
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Correspondence to Brandon L. Pierce.

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Delgado, D.A., Zhang, C., Gleason, K. et al. The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans. Hum Genet 138, 49–60 (2019). https://doi.org/10.1007/s00439-018-1964-2

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