WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene
Nersisyan L., Nikoghosyan M., Arakelyan A., Francioli LC., Menelaou A., Pulit SL., Elbers CC., Kloosterman WP., van Setten J., Nijman IJ., Renkens I., de Bakker PIW., van Dijk F., Neerincx PBT., Deelen P., Kanterakis A., Dijkstra M., Byelas H., van der Velde KJ., Platteel M., Swertz MA., Wijmenga C., Palamara PF., Pe’er I., Ye K., Ye K., Lameijer EW., Moed MH., Beekman M., de Craen AJM., Suchiman HED., Slagboom PE., Guryev V., Abdellaoui A., Jan Hottenga J., Kattenberg M., Willemsen G., Boomsma DI., van Leeuwen EM., Karssen LC., Amin N., Rivadeneira F., Isaacs A., Hofman A., Uitterlinden AG., van Duijn CM., van Oven M., Kayser M., Vermaat M., Laros JFJ., den Dunnen JT., van Enckevort D., Mei H., Li M., Stoneking M., van Schaik BDC., Bot J., Marschall T., Schönhuth A., Hehir-Kwa JY., Handsaker RE., Polak P., Sohail M., Vuzman D., Estrada K., McCarroll SA., Sunyaev SR., Hormozdiari F., Koval V., Medina-Gomez C., Oostra B., Veldink JH., van den Berg LH., Pitts SJ., Potluri S., Sundar P., Cox DR., de Knijff P., Li Q., Li Y., Du Y., Chen R., Cao H., Wang J., Li N., Cao S., Bovenberg JA., van Ommen GJB.
© 2019, The Author(s). Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.