. 2017 May 1;3(5):636-651.

doi: 10.1001/jamaoncol.2016.5945.

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Telomeres Mendelian Randomization Collaboration; Philip C Haycock¹, Stephen Burgess², Aayah Nounu¹, Jie Zheng¹, George N Okoli³, Jack Bowden¹, Kaitlin Hazel Wade¹, Nicholas J Timpson¹, David M Evans⁴, Peter Willeit⁵, Abraham Aviv⁶, Tom R Gaunt¹, Gibran Hemani¹, Massimo Mangino⁷, Hayley Patricia Ellis⁸, Kathreena M Kurian⁸, Karen A Pooley⁹, Rosalind A Eeles¹⁰, Jeffrey E Lee¹¹, Shenying Fang¹¹, Wei V Chen¹², Matthew H Law¹³, Lisa M Bowdler¹⁴, Mark M Iles¹⁵, Qiong Yang¹⁶, Bradford B Worrall¹⁷, Hugh Stephen Markus¹⁸, Rayjean J Hung¹⁹, Chris I Amos²⁰, Amanda B Spurdle²¹, Deborah J Thompson⁹, Tracy A O'Mara²¹, Brian Wolpin²², Laufey Amundadottir²³, Rachael Stolzenberg-Solomon²⁴, Antonia Trichopoulou²⁵, N Charlotte Onland-Moret²⁶, Eiliv Lund²⁷, Eric J Duell²⁸, Federico Canzian²⁹, Gianluca Severi³⁰, Kim Overvad³¹, Marc J Gunter³², Rosario Tumino³³, Ulrika Svenson³⁴, Andre van Rij³⁵, Annette F Baas³⁶, Matthew J Bown³⁷, Nilesh J Samani³⁷, Femke N G van t'Hof³⁸, Gerard Tromp³⁹, Gregory T Jones³⁵, Helena Kuivaniemi³⁹, James R Elmore⁴⁰, Mattias Johansson⁴¹, James Mckay⁴², Ghislaine Scelo⁴¹, Robert Carreras-Torres⁴¹, Valerie Gaborieau⁴¹, Paul Brennan⁴¹, Paige M Bracci⁴³, Rachel E Neale¹⁴, Sara H Olson⁴⁴, Steven Gallinger⁴⁵, Donghui Li⁴⁶, Gloria M Petersen⁴⁷, Harvey A Risch⁴⁸, Alison P Klein⁴⁹, Jiali Han⁵⁰, Christian C Abnet⁵¹, Neal D Freedman⁵¹, Philip R Taylor⁵¹, John M Maris⁵², Katja K Aben⁵³, Lambertus A Kiemeney⁵⁴, Sita H Vermeulen⁵⁴, John K Wiencke⁵⁵, Kyle M Walsh⁵⁵, Margaret Wrensch⁵⁵, Terri Rice⁵⁶, Clare Turnbull⁵⁷, Kevin Litchfield⁵⁸, Lavinia Paternoster¹, Marie Standl⁵⁹, Gonçalo R Abecasis⁶⁰, John Paul SanGiovanni⁶¹, Yong Li⁶², Vladan Mijatovic⁶³, Yadav Sapkota¹⁴, Siew-Kee Low⁶⁴, Krina T Zondervan⁶⁵, Grant W Montgomery¹⁴, Dale R Nyholt⁶⁶, David A van Heel⁶⁷, Karen Hunt⁶⁷, Dan E Arking⁶⁸, Foram N Ashar⁶⁸, Nona Sotoodehnia⁶⁹, Daniel Woo⁷⁰, Jonathan Rosand⁷¹, Mary E Comeau⁷², W Mark Brown⁷², Edwin K Silverman⁷³, John E Hokanson⁷⁴, Michael H Cho⁷³, Jennie Hui⁷⁵, Manuel A Ferreira¹⁴, Philip J Thompson⁷⁶, Alanna C Morrison⁷⁷, Janine F Felix⁷⁸, Nicholas L Smith⁷⁹, Angela M Christiano⁸⁰, Lynn Petukhova⁸¹, Regina C Betz⁸², Xing Fan⁸³, Xuejun Zhang⁸³, Caihong Zhu⁸³, Carl D Langefeld⁷², Susan D Thompson⁸⁴, Feijie Wang⁸⁵, Xu Lin⁸⁵, David A Schwartz⁸⁶, Tasha Fingerlin⁸⁷, Jerome I Rotter⁸⁸, Mary Frances Cotch⁸⁹, Richard A Jensen⁹⁰, Matthias Munz⁹¹, Henrik Dommisch⁹², Arne S Schaefer⁹², Fang Han⁹³, Hanna M Ollila⁹⁴, Ryan P Hillary⁹⁴, Omar Albagha⁹⁵, Stuart H Ralston⁹⁶, Chenjie Zeng⁹⁷, Wei Zheng⁹⁷, Xiao-Ou Shu⁹⁷, Andre Reis⁹⁸, Steffen Uebe⁹⁸, Ulrike Hüffmeier⁹⁸, Yoshiya Kawamura⁹⁹, Takeshi Otowa¹⁰⁰, Tsukasa Sasaki¹⁰¹, Martin Lloyd Hibberd¹⁰², Sonia Davila¹⁰³, Gang Xie¹⁰⁴, Katherine Siminovitch¹⁰⁴, Jin-Xin Bei¹⁰⁵, Yi-Xin Zeng¹⁰⁶, Asta Försti¹⁰⁷, Bowang Chen¹⁰⁸, Stefano Landi¹⁰⁹, Andre Franke¹¹⁰, Annegret Fischer¹¹¹, David Ellinghaus¹¹², Carlos Flores¹¹³, Imre Noth¹¹⁴, Shwu-Fan Ma¹¹⁴, Jia Nee Foo¹¹⁵, Jianjun Liu¹¹⁵, Jong-Won Kim¹¹⁶, David G Cox¹¹⁷, Olivier Delattre¹¹⁸, Olivier Mirabeau¹¹⁸, Christine F Skibola¹¹⁹, Clara S Tang¹²⁰, Merce Garcia-Barcelo¹²⁰, Kai-Ping Chang¹²¹, Wen-Hui Su¹²², Yu-Sun Chang¹²³, Nicholas G Martin¹⁴, Scott Gordon¹⁴, Tracey D Wade¹²⁴, Chaeyoung Lee¹²⁵, Michiaki Kubo¹²⁶, Pei-Chieng Cha¹²⁷, Yusuke Nakamura¹²⁸, Daniel Levy¹²⁹, Masayuki Kimura⁶, Shih-Jen Hwang¹²⁹, Steven Hunt¹³⁰, Tim Spector¹³¹, Nicole Soranzo¹³², Ani W Manichaikul¹³³, R Graham Barr¹³⁴, Bratati Kahali¹³⁵, Elizabeth Speliotes¹³⁵, Laura M Yerges-Armstrong¹³⁶, Ching-Yu Cheng¹³⁷, Jost B Jonas¹³⁸, Tien Yin Wong¹³⁷, Isabella Fogh¹³⁹, Kuang Lin¹³⁹, John F Powell¹³⁹, Kenneth Rice¹⁴⁰, Caroline L Relton¹, Richard M Martin¹⁴¹, George Davey Smith¹

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England.
² Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
³ School of Social and Community Medicine, University of Bristol, Bristol, England.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England4University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge, England5Department of Neurology, Innsbruck Medical University, Austria.
⁶ Center of Human Development and Aging, Department of Pediatrics, New Jersey Medical School, Rutgers, The State University of New Jersey.
⁷ Department of Twin Research and Genetic Epidemiology, King's College London, London England8NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, England.
⁸ Brain Tumour Research Group, Institute of Clinical Neuroscience, Learning and Research Building, Southmead Hospital, University of Bristol.
⁹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
¹⁰ The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, England.
¹¹ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
¹² Department of Clinical Applications & Support, The University of Texas MD Anderson Cancer Center, Houston.
¹³ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁴ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁵ Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, England.
¹⁶ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
¹⁷ Departments of Neurology and Public Health Sciences, University of Virginia Charlottesville, Virginia.
¹⁸ Department of Clinical Neurosciences, University of Cambridge, England.
¹⁹ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada21Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
²⁰ Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
²¹ Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²² Dana-Farber Cancer Institute, Boston, Massachusetts.
²³ Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
²⁴ Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
²⁵ Hellenic Health Foundation, Athens, Greece28WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.
²⁶ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands.
²⁷ Institute of Community Medicine, UiT The Arctic University of Norway, Tromso, Norway.
²⁸ Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
²⁹ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France34Institut Gustave Roussy, Villejuif, France35Human Genetics Foundation (HuGeF), Torino, Italy36Cancer Council Victoria and University of Melbourne, Melbourne, Australia.
³¹ Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
³² School of Public Health, Imperial College London, London, England.
³³ Cancer Registry, Azienda Ospedaliera "Civile M.P. Arezzo," Ragusa, Italy.
³⁴ Department of Medical Biosciences, Umea University, Umea, Sweden.
³⁵ Surgery Department, University of Otago, Dunedin, New Zealand.
³⁶ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
³⁷ Department of Cardiovascular Sciences and the NIHR Leicester, Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Leicester, England.
³⁸ Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.
³⁹ Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa46The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania.
⁴⁰ Department of Vascular and Endovascular Surgery, Geisinger Health System, Danville, Pennsylvania.
⁴¹ Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
⁴² Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
⁴³ Department of Epidemiology and Biostatistics, University of California San Francisco.
⁴⁴ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
⁴⁵ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
⁴⁶ Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
⁴⁷ Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
⁴⁸ Yale School of Public Health, Yale School of Medicine, and Yale Cancer Center, New Haven, Connecticut.
⁴⁹ Departments of Oncology, Pathology and Epidemiology, Johns Hopkins School of Medicine, Baltimore, Maryland.
⁵⁰ Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis57Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.
⁵¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
⁵² Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania.
⁵³ Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands61Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands.
⁵⁴ Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
⁵⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California63Institute of Human Genetics, University of California, San Francisco, San Francisco, California.
⁵⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
⁵⁷ The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, England64William Harvey Research Institute, Queen Mary University, London, England.
⁵⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, England.
⁵⁹ Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁶⁰ Department of Biostatistics, University of Michigan, Ann Arbor.
⁶¹ National Institute of Alcohol Abuse and Alcoholism, Laboratory of Membrane Biophysics and Biochemistry, Section on Nutritional Neuroscience, Bethesda, Maryland69Department of Biochemistry and Molecular and Cellular Biology, Georgetown School of Medicine, Washington, DC.
⁶² Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Faculty of Medicine, and Medical Centre, University of Freiburg, Freiburg, Germany.
⁶³ Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
⁶⁴ Laboratory of Statistical Analysis, Centre for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
⁶⁵ Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England74Nuffield Department of Obstetrics and Gynecology, University of Oxford, John Radcliffe Hospital, Oxford, England.
⁶⁶ QIMR Berghofer Medical Research Institute, Brisbane, Australia75Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
⁶⁷ Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, England.
⁶⁸ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁶⁹ Division of Cardiology and Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
⁷⁰ University of Cincinnati College of Medicine, Department of Neurology, Cincinnati, Ohio.
⁷¹ Massachusetts General Hospital, Neurology, Center for Human Genetic Research, Boston, Massachusetts.
⁷² Center for Public Health Genomics, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
⁷³ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
⁷⁴ Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
⁷⁵ Busselton Population Medical Research Institute Inc, Sir Charles Gairdner Hospital, Perth, Australia85PathWest Laboratory Medicine of Western Australia, Perth, Australia86School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia87School of Population Health, University of WA, Perth, Australia.
⁷⁶ The Lung Health Clinic and Institute for Respiratory Health, University of Western Australia, Perth, Australia.
⁷⁷ Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center at Houston, Houston.
⁷⁸ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁷⁹ Department of Epidemiology, University of Washington, Seattle.
⁸⁰ Departments of Dermatology and Genetics & Development, Columbia University, New York, New York.
⁸¹ Departments of Dermatology and Epidemiology, Columbia University, New York, New York.
⁸² Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁸³ Institute of Dermatology & Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
⁸⁴ Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
⁸⁵ Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁸⁶ Department of Medicine, School of Medicine, University of Colorado, Aurora.
⁸⁷ Department of Biomedical Research, National Jewish Health Hospital, Denver, Colorado.
⁸⁸ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California101Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, California.
⁸⁹ Epidemiology Branch, Division of Epidemiology and Clinical Applications, Intramural Research Program, National Eye Institute, National Institutes of Health, Clinical Research Center, Bethesda, Maryland.
⁹⁰ Cardiovascular Health Research Unit, University of Washington, Seattle104Department of Medicine, University of Washington, Seattle.
⁹¹ Department of Periodontology and Synoptic Dentistry, Center for Dental and Craniofacial Sciences, Charité - University Medicine Berlin, Berlin, Germany106Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
⁹² Department of Periodontology and Synoptic Dentistry, Center for Dental and Craniofacial Sciences, Charité - University Medicine Berlin, Berlin, Germany.
⁹³ Department of Pulmonary Medicine, Peking University People's Hospital, Beijing, China.
⁹⁴ Stanford University, Center for Sleep Sciences, Palo Alto, California.
⁹⁵ Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar110Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
⁹⁶ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
⁹⁷ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
⁹⁸ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁹⁹ Department of Psychiatry, Shonan Kamakura General Hospital, Kanagawa, Japan.
¹⁰⁰ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan115Graduate School of Clinical Psychology, Teikyo Heisei University Major of Professional Clinical Psychology, Tokyo, Japan.
¹⁰¹ Department of Physical and Health Education, Graduate School of Education, University of Tokyo, Tokyo, Japan.
¹⁰² Infectious Diseases, Genome Institute of Singapore, Singapore.
¹⁰³ Human Genetics, Genome Institute of Singapore, Singapore.
¹⁰⁴ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada119Departments of Medicine, Immunology, Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁰⁵ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
¹⁰⁶ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China121Peking Union Medical College, Beijing, China.
¹⁰⁷ Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany123Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
¹⁰⁸ Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰⁹ Department of Biology, University of Pisa, Pisa, Italy.
¹¹⁰ University Hospital Schleswig-Holstein, Kiel, Germany.
¹¹¹ University Hospital Schleswig-Holstein, Kiel, Germany126Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
¹¹² Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
¹¹³ Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Tenerife, Spain128CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
¹¹⁴ Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois.
¹¹⁵ Human Genetics, Genome Institute of Singapore, A*STAR, Singapore.
¹¹⁶ Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan, University School of Medicine, Gangnam-gu, Seoul, South Korea.
¹¹⁷ Cancer Research Center of Lyon, INSERM U1052, Lyon, France.
¹¹⁸ Inserm U830, Institut Curie, PSL University, Paris, France.
¹¹⁹ Department of Epidemiology, University of Alabama at Birmingham.
¹²⁰ Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
¹²¹ Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan.
¹²² Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan137Department of Biomedical Sciences, Graduate Institute of Biomedical Sciences, College of Medicine, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
¹²³ Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
¹²⁴ School of Psychology, Flinders University, Adelaide, South Australia.
¹²⁵ School of Systems Biomedical Science, Soongsil University, Dongjak-gu, Seoul, South Korea.
¹²⁶ RIKEN Center for Integrative Medical Science, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan.
¹²⁷ Division of Molecular Brain Science, Kobe University Graduate School of Medicine, Kusunoki-chou, Chuo-ku, Kobe, Japan.
¹²⁸ Center for Personalized Therapeutics, The University of Chicago, Chicago, Illinois.
¹²⁹ The NHLBI's Framingham Heart Study, Framingham, Massachusetts, Population Sciences Branch of the National Heart, Lung, and Blood Institute, Bethesda, Maryland.
¹³⁰ Department of Genetic Medicine, Weill Cornell Medicine in Qatar, Doha, Qatar.
¹³¹ Department of Twin Research and Genetic Epidemiology, King's College London, London England.
¹³² Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton Cambridge, England.
¹³³ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville.
¹³⁴ Department of Medicine and Department of Epidemiology, Columbia University Medical Center, New York, New York.
¹³⁵ Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor.
¹³⁶ Department of Medicine, University of Maryland, Baltimore.
¹³⁷ Singapore Eye Research Institute, Singapore National Eye Center, Singapore152Department of Ophthalmology, National University of Singapore and National University Health System, Singapore153Duke-NUS Medical School, Singapore.
¹³⁸ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing, China155Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Mannheim, Germany.
¹³⁹ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England.
¹⁴⁰ Department of Biostatistics, University of Washington, Seattle.
¹⁴¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England158University of Bristol/University Hospitals Bristol NHS Foundation Trust National Institute for Health Research Bristol Nutrition Biomedical Research Unit, Bristol, England.

PMID: 28241208
PMCID: PMC5638008
DOI: 10.1001/jamaoncol.2016.5945

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Telomeres Mendelian Randomization Collaboration et al. JAMA Oncol. 2017.

. 2017 May 1;3(5):636-651.

doi: 10.1001/jamaoncol.2016.5945.

Authors

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England.
² Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
³ School of Social and Community Medicine, University of Bristol, Bristol, England.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England4University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge, England5Department of Neurology, Innsbruck Medical University, Austria.
⁶ Center of Human Development and Aging, Department of Pediatrics, New Jersey Medical School, Rutgers, The State University of New Jersey.
⁷ Department of Twin Research and Genetic Epidemiology, King's College London, London England8NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, England.
⁸ Brain Tumour Research Group, Institute of Clinical Neuroscience, Learning and Research Building, Southmead Hospital, University of Bristol.
⁹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
¹⁰ The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, England.
¹¹ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
¹² Department of Clinical Applications & Support, The University of Texas MD Anderson Cancer Center, Houston.
¹³ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁴ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁵ Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, England.
¹⁶ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
¹⁷ Departments of Neurology and Public Health Sciences, University of Virginia Charlottesville, Virginia.
¹⁸ Department of Clinical Neurosciences, University of Cambridge, England.
¹⁹ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada21Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
²⁰ Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
²¹ Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²² Dana-Farber Cancer Institute, Boston, Massachusetts.
²³ Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
²⁴ Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
²⁵ Hellenic Health Foundation, Athens, Greece28WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.
²⁶ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands.
²⁷ Institute of Community Medicine, UiT The Arctic University of Norway, Tromso, Norway.
²⁸ Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
²⁹ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France34Institut Gustave Roussy, Villejuif, France35Human Genetics Foundation (HuGeF), Torino, Italy36Cancer Council Victoria and University of Melbourne, Melbourne, Australia.
³¹ Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
³² School of Public Health, Imperial College London, London, England.
³³ Cancer Registry, Azienda Ospedaliera "Civile M.P. Arezzo," Ragusa, Italy.
³⁴ Department of Medical Biosciences, Umea University, Umea, Sweden.
³⁵ Surgery Department, University of Otago, Dunedin, New Zealand.
³⁶ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
³⁷ Department of Cardiovascular Sciences and the NIHR Leicester, Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Leicester, England.
³⁸ Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.
³⁹ Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa46The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania.
⁴⁰ Department of Vascular and Endovascular Surgery, Geisinger Health System, Danville, Pennsylvania.
⁴¹ Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
⁴² Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
⁴³ Department of Epidemiology and Biostatistics, University of California San Francisco.
⁴⁴ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
⁴⁵ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
⁴⁶ Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
⁴⁷ Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
⁴⁸ Yale School of Public Health, Yale School of Medicine, and Yale Cancer Center, New Haven, Connecticut.
⁴⁹ Departments of Oncology, Pathology and Epidemiology, Johns Hopkins School of Medicine, Baltimore, Maryland.
⁵⁰ Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis57Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.
⁵¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
⁵² Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania.
⁵³ Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands61Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands.
⁵⁴ Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
⁵⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California63Institute of Human Genetics, University of California, San Francisco, San Francisco, California.
⁵⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
⁵⁷ The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, England64William Harvey Research Institute, Queen Mary University, London, England.
⁵⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, England.
⁵⁹ Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁶⁰ Department of Biostatistics, University of Michigan, Ann Arbor.
⁶¹ National Institute of Alcohol Abuse and Alcoholism, Laboratory of Membrane Biophysics and Biochemistry, Section on Nutritional Neuroscience, Bethesda, Maryland69Department of Biochemistry and Molecular and Cellular Biology, Georgetown School of Medicine, Washington, DC.
⁶² Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Faculty of Medicine, and Medical Centre, University of Freiburg, Freiburg, Germany.
⁶³ Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
⁶⁴ Laboratory of Statistical Analysis, Centre for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
⁶⁵ Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England74Nuffield Department of Obstetrics and Gynecology, University of Oxford, John Radcliffe Hospital, Oxford, England.
⁶⁶ QIMR Berghofer Medical Research Institute, Brisbane, Australia75Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
⁶⁷ Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, England.
⁶⁸ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁶⁹ Division of Cardiology and Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
⁷⁰ University of Cincinnati College of Medicine, Department of Neurology, Cincinnati, Ohio.
⁷¹ Massachusetts General Hospital, Neurology, Center for Human Genetic Research, Boston, Massachusetts.
⁷² Center for Public Health Genomics, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
⁷³ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
⁷⁴ Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
⁷⁵ Busselton Population Medical Research Institute Inc, Sir Charles Gairdner Hospital, Perth, Australia85PathWest Laboratory Medicine of Western Australia, Perth, Australia86School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia87School of Population Health, University of WA, Perth, Australia.
⁷⁶ The Lung Health Clinic and Institute for Respiratory Health, University of Western Australia, Perth, Australia.
⁷⁷ Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center at Houston, Houston.
⁷⁸ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁷⁹ Department of Epidemiology, University of Washington, Seattle.
⁸⁰ Departments of Dermatology and Genetics & Development, Columbia University, New York, New York.
⁸¹ Departments of Dermatology and Epidemiology, Columbia University, New York, New York.
⁸² Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁸³ Institute of Dermatology & Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
⁸⁴ Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
⁸⁵ Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁸⁶ Department of Medicine, School of Medicine, University of Colorado, Aurora.
⁸⁷ Department of Biomedical Research, National Jewish Health Hospital, Denver, Colorado.
⁸⁸ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California101Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, California.
⁸⁹ Epidemiology Branch, Division of Epidemiology and Clinical Applications, Intramural Research Program, National Eye Institute, National Institutes of Health, Clinical Research Center, Bethesda, Maryland.
⁹⁰ Cardiovascular Health Research Unit, University of Washington, Seattle104Department of Medicine, University of Washington, Seattle.
⁹¹ Department of Periodontology and Synoptic Dentistry, Center for Dental and Craniofacial Sciences, Charité - University Medicine Berlin, Berlin, Germany106Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
⁹² Department of Periodontology and Synoptic Dentistry, Center for Dental and Craniofacial Sciences, Charité - University Medicine Berlin, Berlin, Germany.
⁹³ Department of Pulmonary Medicine, Peking University People's Hospital, Beijing, China.
⁹⁴ Stanford University, Center for Sleep Sciences, Palo Alto, California.
⁹⁵ Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar110Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
⁹⁶ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
⁹⁷ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
⁹⁸ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁹⁹ Department of Psychiatry, Shonan Kamakura General Hospital, Kanagawa, Japan.
¹⁰⁰ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan115Graduate School of Clinical Psychology, Teikyo Heisei University Major of Professional Clinical Psychology, Tokyo, Japan.
¹⁰¹ Department of Physical and Health Education, Graduate School of Education, University of Tokyo, Tokyo, Japan.
¹⁰² Infectious Diseases, Genome Institute of Singapore, Singapore.
¹⁰³ Human Genetics, Genome Institute of Singapore, Singapore.
¹⁰⁴ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada119Departments of Medicine, Immunology, Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁰⁵ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
¹⁰⁶ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China121Peking Union Medical College, Beijing, China.
¹⁰⁷ Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany123Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
¹⁰⁸ Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰⁹ Department of Biology, University of Pisa, Pisa, Italy.
¹¹⁰ University Hospital Schleswig-Holstein, Kiel, Germany.
¹¹¹ University Hospital Schleswig-Holstein, Kiel, Germany126Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
¹¹² Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
¹¹³ Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Tenerife, Spain128CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
¹¹⁴ Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois.
¹¹⁵ Human Genetics, Genome Institute of Singapore, A*STAR, Singapore.
¹¹⁶ Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan, University School of Medicine, Gangnam-gu, Seoul, South Korea.
¹¹⁷ Cancer Research Center of Lyon, INSERM U1052, Lyon, France.
¹¹⁸ Inserm U830, Institut Curie, PSL University, Paris, France.
¹¹⁹ Department of Epidemiology, University of Alabama at Birmingham.
¹²⁰ Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
¹²¹ Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan.
¹²² Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan137Department of Biomedical Sciences, Graduate Institute of Biomedical Sciences, College of Medicine, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
¹²³ Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
¹²⁴ School of Psychology, Flinders University, Adelaide, South Australia.
¹²⁵ School of Systems Biomedical Science, Soongsil University, Dongjak-gu, Seoul, South Korea.
¹²⁶ RIKEN Center for Integrative Medical Science, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan.
¹²⁷ Division of Molecular Brain Science, Kobe University Graduate School of Medicine, Kusunoki-chou, Chuo-ku, Kobe, Japan.
¹²⁸ Center for Personalized Therapeutics, The University of Chicago, Chicago, Illinois.
¹²⁹ The NHLBI's Framingham Heart Study, Framingham, Massachusetts, Population Sciences Branch of the National Heart, Lung, and Blood Institute, Bethesda, Maryland.
¹³⁰ Department of Genetic Medicine, Weill Cornell Medicine in Qatar, Doha, Qatar.
¹³¹ Department of Twin Research and Genetic Epidemiology, King's College London, London England.
¹³² Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton Cambridge, England.
¹³³ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville.
¹³⁴ Department of Medicine and Department of Epidemiology, Columbia University Medical Center, New York, New York.
¹³⁵ Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor.
¹³⁶ Department of Medicine, University of Maryland, Baltimore.
¹³⁷ Singapore Eye Research Institute, Singapore National Eye Center, Singapore152Department of Ophthalmology, National University of Singapore and National University Health System, Singapore153Duke-NUS Medical School, Singapore.
¹³⁸ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing, China155Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Mannheim, Germany.
¹³⁹ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England.
¹⁴⁰ Department of Biostatistics, University of Washington, Seattle.
¹⁴¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England158University of Bristol/University Hospitals Bristol NHS Foundation Trust National Institute for Health Research Bristol Nutrition Biomedical Research Unit, Bristol, England.

PMID: 28241208
PMCID: PMC5638008
DOI: 10.1001/jamaoncol.2016.5945

Abstract

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data extraction and synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main outcomes and measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions and relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Yerges-Armstrong is a current employee stock-owner at GlaxoSmithKline though the current work was completed while an employee of University of Maryland Baltimore. Dr Worrall is a deputy editorship for the journal Neurology and has received National Institutes of Health funding for sample genotyping. Dr Silverman has received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. Helena Kuivaniemi has received funding from the National Institutes of Health National Heart, Lung, and Blood Institute (HL064310, HL044682), the Pennsylvania Commonwealth Universal Research Enhancement program, the Geisinger Clinical Research Fund, the American Heart Association, the Ben Franklin Technology Development Fund of Pennsylvania, and the National Institutes of Health for sample genotyping (U01HG006382). Dr Eeles has received honoraria from the Genitourinary Cancers Symposium organised by American Society of Clinical Oncology. Dr Rotter has received funding from the National Institutes of Health (R01 HL105756), the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Research Center. No other conflicts reported.

Figures

**Figure 1. The Association Between Genetically Increased Telomere Length and Odds of Primary Noncommunicable Diseases**
COPD indicates chronic obstructive pulmonary disease; ER, estrogen receptor; LMP, low malignancy potential; NA, not applicable; SNP, single-nucleotide polymorphism. ^a P value for association between genetically increased telomere length and disease from maximum likelihood. ^b P value for heterogeneity among SNPs within the instrument. ^c The effect estimate for heart failure is a hazard ratio (all others are odds ratios).

**Figure 2. Comparison of the Present Mendelian Randomization (MR) Study and Prospective Observational Studies of the Association Between Telomere Length and Disease**
Search strategy and characteristics for observational studies are described in eTables 3 and 4 in Supplement 1. ^a From fixed-effects meta-analysis of independent observational studies described in eTable 3 in Supplement 1. ^b From the combination of Copenhagen City Heart Study (CCHS) and Copenhagen General Population Study (CGPS). ^c From the combination of Prostate, Lung, Colorectal, and Ovarian (PLCO), Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and Shanghai Women's Health Study (SWHS).

**Figure 3. The Association Between Genetically Increased Telomere Length and Odds of Cancer as a Function of Selected Characteristics**
A-D, The plotted data show how the strength of the relationship between genetically increased telomere length and cancer varies by the selected characteristic: the R² statistic indicates how much of the variation between cancers can be explained by the selected characteristic; P values are from meta-regression models; circle sizes are proportional to the inverse of the variance of the log OR. A, Data for average lifetime number of stem cell divisions were downloaded from Tomasetti and Vogelstein. B-D, Data for percentage survival 5 years after diagnosis, cancer incidence and median age at diagnosis were downloaded from the Surveillance, Epidemiology, and End Results Program. Not all cancers had information available for the selected characteristics (hence the number of cancers varies across the subplots). Information was available for 9 cancers for tissue-specific rates of stem cell division, 13 cancers for percentage surviving 5 years after diagnosis, 17 cancers for cancer incidence, and 13 cancers for median age at diagnosis. OR indicates odds ratio; SD, standard deviation.

See this image and copyright information in PMC

Comment in

Telomere Length and Risk of Cancer and Non-neoplastic Diseases: Is Survivin the Ariadne's Thread?
Mormile R. Mormile R. JAMA Oncol. 2017 Dec 1;3(12):1740-1741. doi: 10.1001/jamaoncol.2017.2313. JAMA Oncol. 2017. PMID: 28796863 No abstract available.
Telomere Length and Risk of Cancer and Non-neoplastic Diseases: Is Survivin the Ariadne's Thread?-Reply.
Haycock PC, Hemani G, Aviv A. Haycock PC, et al. JAMA Oncol. 2017 Dec 1;3(12):1741-1742. doi: 10.1001/jamaoncol.2017.2316. JAMA Oncol. 2017. PMID: 28796865 No abstract available.

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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

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