The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.We thank J. Dekens for management, A. Maatman and M. Platteel for technical support and K. Mc Intyre for English editing. This project was funded by the BBMRI grant for measuring telomere length and by a Rosalind Franklin Fellowship to A.Z. The researchers participated in this project are supported by Netherlands Heart Foundation (IN-CONTROL CVON grants 2012-03 and 2018-27); the Netherlands Organization for Scientific Research (NWO) Gravitation Netherlands Organ-on-Chip Initiative to J.F. and C.W.; NWO Gravitation Exposome-NL (024.004.017) to J.F., A.K. and A.Z.; NWO-VIDI (864.13.013) and NWO-VICI (VI.C.202.022) to J.F.; NWO-VIDI (016.178.056) to A.Z.; NWO-VIDI (917.14.374) to L.F.; NWO-VENI (194.006) to D.V.Z.; NWO-VENI (192.029) to M.W.; NWO Spinoza Prize SPI 92–266 to C.W.; the European Research Council (ERC) (FP7/2007–2013/ERC Advanced Grant 2012-322698) to C.W.; ERC Starting grant 637640 to L.F.; ERC Starting Grant 715772 to A.Z.; ERC Consolidator Grant (grant agreement No. 101001678) to J.F.; and RuG Investment Agenda Grant Personalized Health to C.W. MM work is supported by RYC- 2017-22249 and PID2019-107937GA-I00 grants. T.S. holds scholarships from the Junior Scientific Masterclass, University of Groningen[grant no. 17–34]. AR is funded by a Formación Personal Investigador (FPI) grant [grant no. PRE2019-090193]. The Lifelines Biobank initiative has been made possible by a subsidy from the Dutch Ministry of Health, Welfare and Sport; the Dutch Ministry of Economic Affairs; the University Medical Centre Groningen (UMCG, the Netherlands); the University of Groningen and the Northern Provinces of the Netherlands. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centres delivering data to Lifelines and all the study participants. Finally, we would like to acknowledge the Genomics Coordination Centre (GCC) at the University Medical College Groningen for the HPC support and the MOLGENIS team for the cloud storage of the data associated with this work.Peer Reviewed"Article signat per 16 autors/es: Sergio Andreu-Sánchez, Geraldine Aubert, Aida Ripoll-Cladellas, Sandra Henkelman, Daria V. Zhernakova, Trishla Sinha, Alexander Kurilshikov, Maria Carmen Cenit, Marc Jan Bonder, Lude Franke, Cisca Wijmenga, Jingyuan Fu, Monique G. P. van der Wijst, Marta Melé, Peter Lansdorp & Alexandra Zhernakova"Postprint (published version
