Letter

Identification of seven loci affecting mean telomere length and their association with disease

Received:
Accepted:
Published online:

Abstract

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10−8). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5–35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

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Acknowledgements

This study was undertaken under the framework of European Union Framework 7 ENGAGE Project (HEALTH-F4-2007-201413). A full list of acknowledgments, including support for each study, is provided in the Supplementary Note.

Author information

Author notes

    • Veryan Codd
    • , Christopher P Nelson
    • , Eva Albrecht
    • , Massimo Mangino
    •  & Pim van der Harst

    These authors contributed equally to this work.

Affiliations

  1. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

    • Veryan Codd
    • , Christopher P Nelson
    • , Mary K Matthews
    • , Peter S Braund
    • , Matthew Denniff
    • , Elena Dubinina
    • , Helen Pollard
    • , Pim van der Harst
    •  & Nilesh J Samani
  2. National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • Veryan Codd
    • , Christopher P Nelson
    •  & Nilesh J Samani
  3. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Eva Albrecht
    •  & Christian Gieger
  4. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Massimo Mangino
    • , Ana M Valdes
    • , Ana Viñuela
    •  & Tim D Spector
  5. Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

    • Joris Deelen
    • , Marian Beekman
    • , H Eka D Suchiman
    •  & P Eline Slagboom
  6. Netherlands Consortium for Healthy Aging, Leiden University Medical Center, Leiden, The Netherlands.

    • Joris Deelen
    • , Linda Broer
    • , Marian Beekman
    • , Jeanine J Houwing-Duistermaat
    • , Cornelia M van Duijn
    •  & P Eline Slagboom
  7. Section of Investigative Medicine, Imperial College London, London, UK.

    • Jessica L Buxton
    •  & Alexandra I F Blakemore
  8. Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.

    • Jouke Jan Hottenga
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  9. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Krista Fischer
    • , Tõnu Esko
    • , Konstantinos Douroudis
    • , Reedik Mägi
    • , Evelin Mihailov
    • , Markus Perola
    •  & Andres Metspalu
  10. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

    • Ida Surakka
    • , Johannes Kettunen
    • , Samuli Ripatti
    • , Elisabeth Widen
    • , Markus Perola
    •  & Jaakko Kaprio
  11. Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Ida Surakka
    • , Perttu Salo
    • , Johan G Eriksson
    • , Johannes Kettunen
    • , Satu Männistö
    • , Samuli Ripatti
    • , Veikko Salomaa
    •  & Markus Perola
  12. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Linda Broer
    • , Najaf Amin
    • , Lennart C Karssen
    • , Elisabeth M van Leeuwen
    • , Ben A Oostra
    •  & Cornelia M van Duijn
  13. Centre for Medical Systems Biology, Leiden, The Netherlands.

    • Linda Broer
    •  & Cornelia M van Duijn
  14. Queensland Institute of Medical Research, Brisbane, Australia.

    • Dale R Nyholt
    • , Anjali K Henders
    • , Sarah E Medland
    • , Grant W Montgomery
    • , Margaret J Wright
    •  & Nicholas G Martin
  15. Department of Cardiology, University of Groningen, University Medical Center, Groningen, The Netherlands.

    • Irene Mateo Leach
    • , Rudolf A de Boer
    • , Niek Verweij
    • , Dirk J van Veldhuisen
    • , Wiek H van Gilst
    •  & Pim van der Harst
  16. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Sara Hägg
    • , Patrik K E Magnusson
    •  & Nancy L Pedersen
  17. Institute of Cardiovascular Science, Univerisity College London, London, UK.

    • Jutta Palmen
    •  & Philippa J Talmud
  18. Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

    • Giuseppe D Norata
    •  & Alberico L Catapano
  19. Centro Societa Italiana per lo Studio dell'Aterosclerosi, Bassini Hospital, Cinisello B, Italy.

    • Giuseppe D Norata
    •  & Katia Garlaschelli
  20. The Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University, London, UK.

    • Giuseppe D Norata
  21. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.

    • Paul F O'Reilly
    •  & Marjo-Riitta Jarvelin
  22. Medical Research Council–Health Protection Agency Centre for Environment and Health, Faculty of Medicine, Imperial College London, London, UK.

    • Paul F O'Reilly
    •  & Marjo-Riitta Jarvelin
  23. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Danish Saleheen
  24. Center for Non-Communicable Diseases, Karachi, Pakistan.

    • Danish Saleheen
  25. Division of Epidemiology, Leeds Institute of Genetics, Health and Therapeutics, School of Medicine, University of Leeds, Leeds, UK.

    • Anthony J Balmforth
    •  & Alistair S Hall
  26. Section of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.

    • Stefan Böhringer
    •  & Jeanine J Houwing-Duistermaat
  27. Department of Health Sciences, University of Leicester, Leicester, UK.

    • Paul R Burton
    • , Martin D Tobin
    •  & John R Thompson
  28. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.

    • Anton J Mde Craen
  29. Georgia Prevention Institute, Georgia Health Sciences University, Augusta, Georgia, USA.

    • Yanbin Dong
    • , Dehuang Guo
    • , Xiaoling Wang
    •  & Haidong Zhu
  30. University of Helsinki, Department of General Practice and Primary Health Care, Helsinki, Finland.

    • Johan G Eriksson
  31. Folkhälsan Research Center, Helsinki, Finland.

    • Johan G Eriksson
  32. Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.

    • Johan G Eriksson
  33. Institute of Clinical Medicine/Obstetrics and Gynecology, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
    •  & Anneli Pouta
  34. Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

    • Laura Kananen
    •  & Iiris Hovatta
  35. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.

    • Laura Kananen
    •  & Iiris Hovatta
  36. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Norman Klopp
    •  & Annette Peters
  37. Hanover Unified Biobank, Hanover Medical School, Hanover, Germany.

    • Norman Klopp
  38. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Vasiliki Lagou
    • , Mark I McCarthy
    •  & Inga Prokopenko
  39. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Pamela A Madden
  40. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Mark I McCarthy
  41. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  42. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Aarno Palotie
    • , Samuli Ripatti
    •  & Willem Ouwehand
  43. Department of Medical Genetics, University of Helsinki and the Helsinki University Hospital, Helsinki, Finland.

    • Aarno Palotie
  44. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Annette Peters
  45. Munich Heart Alliance, Munich, Germany.

    • Annette Peters
  46. National Institute for Health and Welfare, Oulu, Finland.

    • Anneli Pouta
  47. Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • H-Erich Wichmann
  48. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians Universität, Munich, Germany.

    • H-Erich Wichmann
  49. KlinikumGrosshadern, Munich, Germany.

    • H-Erich Wichmann
  50. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Kai Xia
  51. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Xiangjun Xiao
  52. Instituto di Ricovero e Cura a Carattere Scientifico Multimedica, Milan, Italy.

    • Alberico L Catapano
  53. UniversitätzuLübeck, Medizinische Klinik II, Lübeck, Germany.

    • Jeanette Erdmann
    •  & Heribert Schunkert
  54. The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Muredach P Reilly
  55. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan
  56. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan
  57. Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.

    • Sekar Kathiresan
  58. Department of Hematology, University of Cambridge, Cambridge, UK.

    • Willem Ouwehand
  59. National Health Service Blood and Transplant, Cambridge, UK.

    • Willem Ouwehand
  60. University of Helsinki, Hjelt Institute, Department of Public Health, Helsinki, Finland.

    • Jaakko Kaprio
  61. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Kaprio
    •  & Iiris Hovatta
  62. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  63. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  64. Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  65. Department of Genetics, University of Groningen, University Medical Center, Groningen, The Netherlands.

    • Pim van der Harst

Consortia

  1. CARDIoGRAM consortium

    A full list of members is provided in the Supplementary Note.

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Contributions

V.C. and N.J.S. supervised the overall study. V.C., M.M., T.D.S., P.v.d.H. and N.J.S. designed the study. M.M., T.E., D.R.N., R.A.d.B., G.D.N., D.S., N.A., A.J.B., P.S.B., P.R.B., K.D., M.D., J.G.E., K.G., A.-L.H., A.K.H., L.C. Karssen, J.K., N.K., V.L., I.M.L., E.M.v.L., P.A.M., R.M., P.K.E.M., S.M., M.I.M., S.E.M., E.M., G.W.M., B.A.O., J.P., A. Palotie, A. Peters, Anneli Pouta, I.P., S.R.,V.S., A.M.V., N.V., A.V., H.-E.W., E.W., G.W., M.J.W., K.X., X.X., D.J.v.V., A.L.C., M.D.T., A.S.H., A.I.F.B., P.J.T., N.L.P., M.P., J.D., W.O., J. Kaprio, N.G.M., C.M.v.D., C.G., A.M., D.I.B., M.-R.J., W.H.v.G., P.E.S., T.D.S., P.v.d.H. and N.J.S. contributed to recruitment, study and data management, genotyping and/or imputation of individual studies. V.C., J.L.B., M.K.M., R.A.d.B., J.P., E.D., L.K., H.P., P.T.J. and I.H. measured telomere length. C.P.N., E.A., M.M., J.D., J.L.B., J.J.H., K.F., T.E., I.S., L.B., D.R.N., R.A.d.B., P.S., S.H., G.D.N., P.F.O., I.M.L., S.E.M. and P.v.d.H. undertook association analysis of individual studies; C.P.N., E.A. and J.R.T. carried out the meta-analysis and the additional reported analyses. H.Z., X.W., D.G. and Y.D. provided data on telomerase activity and genotypes. J.E., M.P.R., S.K. and H.S. contributed CAD association data on behalf of CARDIoGRAM. V.C. and N.J.S. prepared the paper together with C.P.N., E.A., M.M. and P.v.d.H. and all authors reviewed the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nilesh J Samani.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3, Supplementary Tables 1–8, Supplementary Note