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

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  • Chen Li, MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom., Storbritannien
  • Svetlana Stoma, Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom LE3 9QP., Storbritannien
  • Luca A Lotta, MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom., Storbritannien
  • Sophie Warner, Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom LE3 9QP., Storbritannien
  • Eva Albrecht, Institute of Epidemiology, Helmholtz Zentrum München-German Research Centre for Environmental Health, D-85764 Neuherberg, Germany., Tyskland
  • Alessandra Allione, Department of Medical Science, Genomic Variation and Translational Research Unit, University of Turin, 10126 Turin, Italy; Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy., Italien
  • Pascal P Arp, Department of Internal Medicine, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands., Holland
  • Linda Broer, Department of Internal Medicine, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands., Holland
  • Jessica L Buxton, School of Life Sciences, Pharmacy, and Chemistry, Kingston University, Kingston upon Thames, KT1 2EE, United Kingdom; Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, United Kingdom., Storbritannien
  • Alexessander Da Silva Couto Alves, School of Public Health, Imperial College London, St Mary's Hospital, London W2 1PG, United Kingdom; School of Biosciences and Medicine, University of Surrey, Guildford, GU2 7XH, United Kingdom., Storbritannien
  • Joris Deelen, Max Planck Institute for Biology of Ageing, D-50931, Cologne, Germany; Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, the Netherlands., Holland
  • Iryna O Fedko, Department of Biological Psychology, Vrije Universteit, 1081 BT Amsterdam, the Netherlands., Holland
  • Scott D Gordon, Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland, 4006 Australia., Australien
  • Tao Jiang, BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, United Kingdom., Storbritannien
  • Robert Karlsson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden., Sverige
  • Nicola Kerrison, MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom., Storbritannien
  • Taylor K Loe, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA., USA
  • Massimo Mangino, Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, United Kingdom; NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London SE1 9RT, United Kingdom., Storbritannien
  • Yuri Milaneschi, Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit, 1081HJ, Amsterdam, the Netherlands., Holland
  • Benjamin Miraglio, Institute for Molecular Medicine Finland (FIMM), PO Box 20, 00014 University of Helsinki, Finland., Finland
  • Natalia Pervjakova, Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia., Estland
  • Alessia Russo, Department of Medical Science, Genomic Variation and Translational Research Unit, University of Turin, 10126 Turin, Italy; Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy., Italien
  • Ida Surakka, Institute for Molecular Medicine Finland (FIMM), PO Box 20, 00014 University of Helsinki, Finland; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA., Finland
  • Ashley van der Spek, Department of Epidemiology, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands., Holland
  • Josine E Verhoeven, Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit, 1081HJ, Amsterdam, the Netherlands., Holland
  • Najaf Amin, Department of Epidemiology, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands., Holland
  • Marian Beekman, Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, the Netherlands., Holland
  • Alexandra I Blakemore, Department of Life Sciences, Brunel University London, Uxbridge UB8 3PH, United Kingdom; Department of Medicine, Imperial College London, London, W12 0HS, United Kingdom., Storbritannien
  • Federico Canzian, Genomic Epidemiology Group, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany., Tyskland
  • Stephen E Hamby, Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom LE3 9QP., Storbritannien
  • Jouke-Jan Hottenga, Department of Biological Psychology, Vrije Universteit, 1081 BT Amsterdam, the Netherlands., Holland
  • Peter D Jones, Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom LE3 9QP., Storbritannien
  • Pekka Jousilahti, Department of Public Health Solutions, Finnish Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland., Finland
  • Reedik Mägi, Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia., Estland
  • Sarah E Medland, Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland, 4006 Australia., Australien
  • Grant W Montgomery, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia., Australien
  • Dale R Nyholt, Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland, 4006 Australia; School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, 4059, Australia., Australien
  • Markus Perola, Department of Public Health Solutions, Finnish Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, Biomedicum 1, PO Box 63, 00014 University of Helsinki, Finland., Finland
  • Kirsi H Pietiläinen, Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland; Obesity Center, Abdominal Center, Endocrinology, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, 00029 HUS, Helsinki, Finland., Finland
  • Veikko Salomaa, Department of Public Health Solutions, Finnish Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland., Finland
  • Elina Sillanpää, Institute for Molecular Medicine Finland (FIMM), PO Box 20, 00014 University of Helsinki, Finland; Gerontology Research Center, Faculty of Sport and Health Sciences, PO Box 35, 40014 University of Jyväskylä, Finland., Finland
  • H Eka Suchiman, Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, the Netherlands., Holland
  • Diana van Heemst, Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, the Netherlands., Holland
  • Gonneke Willemsen, Department of Biological Psychology, Vrije Universteit, 1081 BT Amsterdam, the Netherlands., Holland
  • Antonio Agudo, Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-ICO, Group of Research on Nutrition and Cancer, Bellvitge Biomedical Research Institute-IDIBELL, L'Hospitalet of Llobregat, 08908 Barcelona, Spain., Spanien
  • Heiner Boeing, Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany., Tyskland
  • Dorret I Boomsma, Department of Biological Psychology, Vrije Universteit, 1081 BT Amsterdam, the Netherlands., Holland
  • Maria-Dolores Chirlaque, Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, 30008, Murcia, Spain; CIBER of Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain., Spanien
  • Guy Fagherazzi, Center of Research in Epidemiology and Population Health, UMR 1018 Inserm, Institut Gustave Roussy, Paris-Sud Paris-Saclay University, 94805 Villejuif, France; Digital Epidemiology Research Hub, Department of Population Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg., Luxemborg
  • Pietro Ferrari, International Agency for Research on Cancer, 69372 Lyon, France., Frankrig
  • Paul Franks, Department of Clinical Sciences, Clinical Research Center, Skåne University Hospital, Lund University, 20502 Malmö, Sweden; Department of Public Health and Clinical Medicine, Umeå University, 90187 Umeå, Sweden., Sverige
  • Christian Gieger, Institute of Epidemiology, Helmholtz Zentrum München-German Research Centre for Environmental Health, D-85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), D-85764 Neuherberg, Germany., Tyskland
  • Johan Gunnar Eriksson, Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland; Folkhälsan Research Centre, PO Box 20, 00014 University of Helsinki, Finland; Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597., Singapore
  • Marc Gunter, International Agency for Research on Cancer, 69372 Lyon, France.
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  • Sara Hägg, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden., Sverige
  • Iiris Hovatta, SleepWell Research Program, Haartmaninkatu 3, 00014 University of Helsinki, Finland; Department of Psychology and Logopedics, Haartmaninkatu 3, 00014 University of Helsinki, Finland., Finland
  • Liher Imaz, Ministry of Health of the Basque Government, Public Health Division of Gipuzkoa, 20013 Donostia-San Sebastian, Spain; Biodonostia Health Research Institute, 20014 Donostia-San Sebastian, Spain., Spanien
  • Jaakko Kaprio, Institute for Molecular Medicine Finland (FIMM), PO Box 20, 00014 University of Helsinki, Finland; Department of Public Health, PO Box 20, 00014 University of Helsinki, Finland., Finland
  • Rudolf Kaaks, Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. r.kaaks@dkfz-heidelberg.de., Tyskland
  • Timothy Key, Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Oxford OX3 7LF, United Kingdom., Storbritannien
  • Vittorio Krogh, Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy., Italien
  • Nicholas G Martin, Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland, 4006 Australia., Australien
  • Olle Melander, Department of Clinical Sciences, Hypertension, and Cardiovascular Disease, Lund University, 21428 Malmö, Sweden., Sverige
  • Andres Metspalu, Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia., Estland
  • Concha Moreno, Instituto de Salud Pública, 31003 Pamplona, Spain., Spanien
  • N Charlotte Onland-Moret, Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 Utrecht, The Netherlands., Holland
  • Peter Nilsson, Department of Clinical Sciences, Clinical Research Center, Skåne University Hospital, Lund University, 20502 Malmö, Sweden., Sverige
  • Ken K Ong, MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom; Department of Paediatrics, University of Cambridge, CB2 0QQ, United Kingdom., Storbritannien
  • Kim Overvad
  • Domenico Palli, Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research-ISPRO, 50139 Florence, Italy., Italien
  • Salvatore Panico, Dipartimento di Medicina Clinica e Chirurgia, Federico II University, 80131 Naples, Italy., Italien
  • Nancy L Pedersen, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden., Sverige
  • Brenda W J H Penninx, Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit, 1081HJ, Amsterdam, the Netherlands., Holland
  • J Ramón Quirós, Consejería de Sanidad, Public Health Directorate, 33006 Asturias, Spain., Spanien
  • Marjo Riitta Jarvelin, School of Public Health, Imperial College London, St Mary's Hospital, London W2 1PG, United Kingdom; School of Epidemiology and Biostatistics, Imperial College London, SW7 2AZ, United Kingdom., Storbritannien
  • Miguel Rodríguez-Barranco, Center of Research in Epidemiology and Population Health, UMR 1018 Inserm, Institut Gustave Roussy, Paris-Sud Paris-Saclay University, 94805 Villejuif, France; Andalusian School of Public Health (EASP), 18080 Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain., Frankrig
  • Robert A Scott, MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom., Storbritannien
  • Gianluca Severi, CESP, Facultés de médecine, Université Paris, 94805 Villejuif, France; Gustave Roussy, 94805 Villejuif, France; Department of Statistics, Computer Science, Applications "G. Parenti," University of Florence, 50134 Firenze, Italy., Italien
  • P Eline Slagboom, Max Planck Institute for Biology of Ageing, D-50931, Cologne, Germany; Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, the Netherlands., Holland
  • Tim D Spector, Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, United Kingdom., Storbritannien
  • Anne Tjonneland, Danish Cancer Society Research Center, Danish Cancer Society, Strandboulevarden 49, 2100, Copenhagen Ø, Denmark. skriver@cancer.dk., Danmark
  • Antonia Trichopoulou, Hellenic Health Foundation, Alexandroupoleos 23, Athens, 11527, Greece., Grækenland
  • Rosario Tumino, Cancer Registry and Histopathology Department, Provincial Health Authority (ASP), 97100 Ragusa, Italy; Hyblean Association for Research on Epidemiology, No Profit Organization, 97100 Ragusa, Italy., Italien
  • André G Uitterlinden, Department of Internal Medicine, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands., Holland
  • Yvonne T van der Schouw, Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 Utrecht, The Netherlands., Holland
  • Cornelia M van Duijn, Department of Epidemiology, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands; Nuffield Department of Population Health, University of Oxford, OX3 7LF, United Kingdom., Holland
  • Elisabete Weiderpass, International Agency for Research on Cancer, 69372 Lyon, France., Frankrig
  • Eros Lazzerini Denchi, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Laboratory of Chromosome Instability, National Cancer Institute, NIH, Bethesda, MD 20892 USA., USA
  • Giuseppe Matullo, Department of Medical Science, Genomic Variation and Translational Research Unit, University of Turin, 10126 Turin, Italy; Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy., Italien
  • Adam S Butterworth, BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, CB10 1SA, United Kingdom; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, United Kingdom; BHF Cambridge Centre of Excellence, School of Clinical Medicine, Addenbrookes' Hospital, Cambridge, Storbritannien
  • John Danesh, BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, CB10 1SA, United Kingdom; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, United Kingdom; Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, United Kingdom; BHF Cam, Storbritannien
  • Nilesh J Samani, Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom LE3 9QP., Storbritannien
  • Nicholas J Wareham, MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom., Storbritannien
  • Christopher P Nelson, Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom LE3 9QP., Storbritannien
  • Claudia Langenberg, MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom. Electronic address: Claudia.Langenberg@mrc-epid.cam.ac.uk., Storbritannien
  • Veryan Codd, Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom. Electronic address: vc15@leicester.ac.uk., Storbritannien

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.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind106
Nummer3
Sider (fra-til)389-404
Antal sider16
ISSN0002-9297
DOI
StatusUdgivet - 2020

Bibliografisk note

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

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