Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
32109421
TITLE
Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.
ABSTRACT
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.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2020 03 05
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2019/10/22
accepted 2020/02/10
pubmed 2020/02/29 06:00
medline 2020/05/06 06:00
entrez 2020/02/29 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Li C Li Chen C MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.
Stoma S Stoma Svetlana S Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.
Lotta LA Lotta Luca A LA MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom.
Warner S Warner Sophie S Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom.
Albrecht E Albrecht Eva E Institute of Epidemiology, Helmholtz Zentrum München-German Research Centre for Environmental Health, D-85764 Neuherberg, Germany.
Allione A Allione Alessandra A 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.
Arp PP Arp Pascal P PP Department of Internal Medicine, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands.
Broer L Broer Linda L Department of Internal Medicine, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands.
Buxton JL Buxton Jessica L JL 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.
Da Silva Couto Alves A Da Silva Couto Alves Alexessander A 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.
Deelen J Deelen Joris J 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.
Fedko IO Fedko Iryna O IO Department of Biological Psychology, Vrije Universteit, 1081 BT Amsterdam, the Netherlands.
Gordon SD Gordon Scott D SD Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland, 4006 Australia.
Jiang T Jiang Tao T BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, United Kingdom.
Karlsson R Karlsson Robert R Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
Kerrison N Kerrison Nicola N MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom.
Loe TK Loe Taylor K TK Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Mangino M Mangino Massimo M 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.
Milaneschi Y Milaneschi Yuri Y Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit, 1081HJ, Amsterdam, the Netherlands.
Miraglio B Miraglio Benjamin B Institute for Molecular Medicine Finland (FIMM), PO Box 20, 00014 University of Helsinki, Finland.
Pervjakova N Pervjakova Natalia N Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia.
Russo A Russo Alessia A 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.
Surakka I Surakka Ida I 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.
van der Spek A van der Spek Ashley A Department of Epidemiology, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands.
Verhoeven JE Verhoeven Josine E JE Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit, 1081HJ, Amsterdam, the Netherlands.
Amin N Amin Najaf N Department of Epidemiology, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands.
Beekman M Beekman Marian M Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, the Netherlands.
Blakemore AI Blakemore Alexandra I AI Department of Life Sciences, Brunel University London, Uxbridge UB8 3PH, United Kingdom; Department of Medicine, Imperial College London, London, W12 0HS, United Kingdom.
Canzian F Canzian Federico F Genomic Epidemiology Group, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
Hamby SE Hamby Stephen E SE Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.
Hottenga JJ Hottenga Jouke-Jan JJ Department of Biological Psychology, Vrije Universteit, 1081 BT Amsterdam, the Netherlands.
Jones PD Jones Peter D PD Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom.
Jousilahti P Jousilahti Pekka P Department of Public Health Solutions, Finnish Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.
Mägi R Mägi Reedik R Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia.
Medland SE Medland Sarah E SE Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland, 4006 Australia.
Montgomery GW Montgomery Grant W GW Institute for Molecular Bioscience, The University of Queensland, 4072, Queensland, Australia.
Nyholt DR Nyholt Dale R DR 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.
Perola M Perola Markus M 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.
Pietiläinen KH Pietiläinen Kirsi H KH 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.
Salomaa V Salomaa Veikko V Department of Public Health Solutions, Finnish Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.
Sillanpää E Sillanpää Elina E 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.
Suchiman HE Suchiman H Eka HE Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, the Netherlands.
van Heemst D van Heemst Diana D Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, the Netherlands.
Willemsen G Willemsen Gonneke G Department of Biological Psychology, Vrije Universteit, 1081 BT Amsterdam, the Netherlands.
Agudo A Agudo Antonio A 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.
Boeing H Boeing Heiner H German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
Boomsma DI Boomsma Dorret I DI Department of Biological Psychology, Vrije Universteit, 1081 BT Amsterdam, the Netherlands.
Chirlaque MD Chirlaque Maria-Dolores MD Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, 30008, Murcia, Spain; CIBER of Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain.
Fagherazzi G Fagherazzi Guy G 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.
Ferrari P Ferrari Pietro P International Agency for Research on Cancer, 69372 Lyon, France.
Franks P Franks Paul P 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.
Gieger C Gieger Christian C 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.
Eriksson JG Eriksson Johan Gunnar JG 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.
Gunter M Gunter Marc M International Agency for Research on Cancer, 69372 Lyon, France.
Hägg S Hägg Sara S Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
Hovatta I Hovatta Iiris I SleepWell Research Program, Haartmaninkatu 3, 00014 University of Helsinki, Finland; Department of Psychology and Logopedics, Haartmaninkatu 3, 00014 University of Helsinki, Finland.
Imaz L Imaz Liher L 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.
Kaprio J Kaprio Jaakko J 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.
Kaaks R Kaaks Rudolf R Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Key T Key Timothy T Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, OX3 7LF, United Kingdom.
Krogh V Krogh Vittorio V Epidemiology and Prevention Unit, Fondazione IRCCS-Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Martin NG Martin Nicholas G NG Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland, 4006 Australia.
Melander O Melander Olle O Department of Clinical Sciences, Hypertension, and Cardiovascular Disease, Lund University, 21428 Malmö, Sweden.
Metspalu A Metspalu Andres A Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia.
Moreno C Moreno Concha C Instituto de Salud Pública, 31003 Pamplona, Spain.
Onland-Moret NC Onland-Moret N Charlotte NC Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands.
Nilsson P Nilsson Peter P Department of Clinical Sciences, Clinical Research Center, Skåne University Hospital, Lund University, 20502 Malmö, Sweden.
Ong KK Ong Ken K KK MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom; Department of Paediatrics, University of Cambridge, CB2 0QQ, United Kingdom.
Overvad K Overvad Kim K Department of Public Health, Aarhus University, DK-8000 Aarhus, Denmark; Department of Cardiology, Aalborg University Hospital, DK-9000 Aalborg, Denmark.
Palli D Palli Domenico D Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research-ISPRO, 50139 Florence, Italy.
Panico S Panico Salvatore S Dipartimento di Medicina Clinica e Chirurgia, Federico II University, 80131 Naples, Italy.
Pedersen NL Pedersen Nancy L NL Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
Penninx BWJH Penninx Brenda W J H BWJH Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit, 1081HJ, Amsterdam, the Netherlands.
Quirós JR Quirós J Ramón JR Consejería de Sanidad, Public Health Directorate, 33006 Asturias, Spain.
Jarvelin MR Jarvelin Marjo Riitta MR 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.
Rodríguez-Barranco M Rodríguez-Barranco Miguel M 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.
Scott RA Scott Robert A RA MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom.
Severi G Severi Gianluca G 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.
Slagboom PE Slagboom P Eline PE 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.
Spector TD Spector Tim D TD Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, United Kingdom.
Tjonneland A Tjonneland Anne A Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
Trichopoulou A Trichopoulou Antonia A Hellenic Health Foundation, 11527 Athens, Greece.
Tumino R Tumino Rosario R Cancer Registry and Histopathology Department, Provincial Health Authority (ASP), 97100 Ragusa, Italy; Hyblean Association for Research on Epidemiology, No Profit Organization, 97100 Ragusa, Italy.
Uitterlinden AG Uitterlinden André G AG Department of Internal Medicine, Erasmus Medical Centre, Postbus 2040, 3000 CA, Rotterdam, the Netherlands.
van der Schouw YT van der Schouw Yvonne T YT Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands.
van Duijn CM van Duijn Cornelia M CM 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.
Weiderpass E Weiderpass Elisabete E International Agency for Research on Cancer, 69372 Lyon, France.
Denchi EL Denchi Eros Lazzerini EL 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.
Matullo G Matullo Giuseppe G 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.
Butterworth AS Butterworth Adam S AS 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, CB2 0QQ, United Kingdom; NIHR Cambridge Biomedical Research Centre, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
Danesh J Danesh John J 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 Cambridge Centre of Excellence, School of Clinical Medicine, Addenbrookes' Hospital, Cambridge, CB2 0QQ, United Kingdom; NIHR Cambridge Biomedical Research Centre, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
Samani NJ Samani Nilesh J NJ Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.
Wareham NJ Wareham Nicholas J NJ MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom.
Nelson CP Nelson Christopher P CP Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.
Langenberg C Langenberg Claudia C MRC Epidemiology Unit, University of Cambridge, CB2 0SL, United Kingdom. Electronic address: Claudia.Langenberg@mrc-epid.cam.ac.uk.
Codd V Codd Veryan V 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.
INVESTIGATORS
JOURNAL
VOLUME: 106
ISSUE: 3
TITLE: American journal of human genetics
ISOABBREVIATION: Am J Hum Genet
YEAR: 2020
MONTH: 03
DAY: 05
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1537-6605
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
MR/L003120/1 Medical Research Council United Kingdom
MC_UU_12015/1 Medical Research Council United Kingdom
MC_UU_12015/2 Medical Research Council United Kingdom
MC_UU_12015/1 Medical Research Council [UK] International
Wellcome Trust United Kingdom
MC_UU_00006/2 Medical Research Council United Kingdom
RG/13/13/30194 British Heart Foundation United Kingdom
GENERAL NOTE
KEYWORDS
KEYWORD
Mendelian randomisation
age-related disease
biological aging
telomere length
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Genome-Wide Association Study
Humans
Leukocytes ultrastructure
Nucleotides metabolism
Telomere metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Nucleotides
OTHER ID's
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