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Genome-Wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

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posted on 2020-05-07, 12:27 authored by Chen Li, Svetlana Stoma, Luca A Lotta, Sophie Warner, Eva Albrecht, Alessandra Allione, Pascal P Arp, Linda Broer, Jessica L Buxton, Alexessander Da Silva Couto Alves, Joris Deelen, Iryna O Fedko, Scott D Gordon, Tao Jiang, Robert Karlsson, Nicola Kerrison, Taylor K Loe, Massimo Mangino, Yuri Milaneschi, Benjamin Miraglio, Natalia Pervjakova, Alessia Russo, Ida Surakka, Ashley van der Spek, Josine E Verhoeven, Najaf Amin, Marian Beekman, Alexandra I Blakemore, Federico Canzian, Stephen E Hamby, Jouke-Jan Hottenga, Peter D Jones, Pekka Jousilahti, Reedik Mägi, Sarah E Medland, Grant W Montgomery, Dale R Nyholt, Markus Perola, Kirsi H Pietiläinen, Veikko Salomaa, Elina Sillanpää, H Eka Suchiman, Diana van Heemst, Gonneke Willemsen, Antonio Agudo, Heiner Boeing, Dorret I Boomsma, Maria-Dolores Chirlaque, Guy Fagherazzi, Pietro Ferrari, Paul Franks, Christian Gieger, Johan Gunnar Eriksson, Marc Gunter, Sara Hägg, Iiris Hovatta, Liher Imaz, Jaakko Kaprio, Rudolf Kaaks, Timothy Key, Vittorio Krogh, Nicholas G Martin, Olle Melander, Andres Metspalu, Concha Moreno, N Charlotte Onland-Moret, Peter Nilsson, Ken K Ong, Kim Overvad, Domenico Palli, Salvatore Panico, Nancy L Pedersen, Brenda WJH Penninx, J Ramón Quirós, Marjo Riitta Jarvelin, Miguel Rodríguez-Barranco, Robert A Scott, Gianluca Severi, P Eline Slagboom, Tim D Spector, Anne Tjonneland, Antonia Trichopoulou, Rosario Tumino, André G Uitterlinden, Yvonne T van der Schouw, Cornelia M van Duijn, Elisabete Weiderpass, Eros Lazzerini Denchi, Giuseppe Matullo, Adam S Butterworth, John Danesh, Nilesh J Samani, Nicholas J Wareham, Christopher P Nelson, Claudia Langenberg, Veryan Codd
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.


The ENGAGE Project was funded under the European Union Framework 7—Health Theme (HEALTH-F4-2007- 201413). The InterAct project received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). The EPIC-CVD study was supported by core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust)[*]. C.P.N is funded by the British Heart Foundation (BHF). V.C., C.P.N., and N.J.S. are supported by the National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Centre and N.J.S. holds an NIHR Senior Investigator award. Chen Li is support by a four-year Wellcome Trust PhD Studentship; C.L., L.A.L., and N.J.W. are funded by the Medical Research Council (MC_UU_12015/1). N.J.W. is an NIHR Senior Investigator. J.D. is funded by the NIHR (Senior Investigator Award).[*]. *The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Cohort-specific and further acknowledgments are given in the Supplemental Information.



American journal of human genetics Volume 106, Issue 3, 5 March 2020, Pages 389-404


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