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

Veryan Codd; Christopher P. Nelson; Eva Albrecht; Massimo Mangino; Joris Deelen; Jessica L. Buxton; Jouke Jan Hottenga; Krista Fischer; Tõnu Esko; Ida Surakka; Linda Broer; Dale R. Nyholt; Irene Mateo Leach; Perttu Salo; Sara Hägg; Mary K. Matthews; Jutta Palmen; Giuseppe D. Norata; Paul F. O'Reilly; Danish Saleheen; Najaf Amin; Anthony J. Balmforth; Marian Beekman; Rudolf A. De Boer; Stefan Böhringer; Peter S. Braund; Paul R. Burton; Anton J.Mde Craen; Matthew Denniff; Yanbin Dong; Konstantinos Douroudis; Elena Dubinina; Johan G. Eriksson; Katia Garlaschelli; Dehuang Guo; Anna Liisa Hartikainen; Anjali K. Henders; Jeanine J. Houwing-Duistermaat; Laura Kananen; Lennart C. Karssen; Johannes Kettunen; Norman Klopp; Vasiliki Lagou; Elisabeth M. Van Leeuwen; Pamela A. Madden; Reedik Mägi; Patrik K.E. Magnusson; Satu Männistö; Mark I. McCarthy; Sarah E. Medland; Evelin Mihailov; Grant W. Montgomery; Ben A. Oostra; Aarno Palotie; Annette Peters; Helen Pollard; Anneli Pouta; Inga Prokopenko; Samuli Ripatti; Veikko Salomaa; H. Eka D. Suchiman; Ana M. Valdes; Niek Verweij; Ana Viñuela; Xiaoling Wang; H. Erich Wichmann; Elisabeth Widen; Gonneke Willemsen; Margaret J. Wright; Kai Xia; Xiangjun Xiao; Dirk J. Van Veldhuisen; Alberico L. Catapano; Martin D. Tobin; Alistair S. Hall; Alexandra I.F. Blakemore; Wiek H. Van Gilst; Haidong Zhu; Jeanette Erdmann; Muredach P. Reilly; Sekar Kathiresan; Heribert Schunkert; Philippa J. Talmud; Nancy L. Pedersen; Markus Perola; Willem Ouwehand; Jaakko Kaprio; Nicholas G. Martin; Cornelia M. Van Duijn; Iiris Hovatta; Christian Gieger; Andres Metspalu; Dorret I. Boomsma; Marjo Riitta Jarvelin; P. Eline Slagboom; John R. Thompson; Tim D. Spector; Pim Van Der Harst; Nilesh J. Samani

doi:10.1038/ng.2528

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

Veryan Codd, Christopher P. Nelson, Eva Albrecht, Massimo Mangino, Joris Deelen, Jessica L. Buxton, Jouke Jan Hottenga, Krista Fischer, Tõnu Esko, Ida Surakka, Linda Broer, Dale R. Nyholt, Irene Mateo Leach, Perttu Salo, Sara Hägg, Mary K. Matthews, Jutta Palmen, Giuseppe D. Norata, Paul F. O'Reilly, Danish SaleheenNajaf Amin, Anthony J. Balmforth, Marian Beekman, Rudolf A. De Boer, Stefan Böhringer, Peter S. Braund, Paul R. Burton, Anton J.Mde Craen, Matthew Denniff, Yanbin Dong, Konstantinos Douroudis, Elena Dubinina, Johan G. Eriksson, Katia Garlaschelli, Dehuang Guo, Anna Liisa Hartikainen, Anjali K. Henders, Jeanine J. Houwing-Duistermaat, Laura Kananen, Lennart C. Karssen, Johannes Kettunen, Norman Klopp, Vasiliki Lagou, Elisabeth M. Van Leeuwen, Pamela A. Madden, Reedik Mägi, Patrik K.E. Magnusson, Satu Männistö, Mark I. McCarthy, Sarah E. Medland, Evelin Mihailov, Grant W. Montgomery, Ben A. Oostra, Aarno Palotie, Annette Peters, Helen Pollard, Anneli Pouta, Inga Prokopenko, Samuli Ripatti, Veikko Salomaa, H. Eka D. Suchiman, Ana M. Valdes, Niek Verweij, Ana Viñuela, Xiaoling Wang, H. Erich Wichmann, Elisabeth Widen, Gonneke Willemsen, Margaret J. Wright, Kai Xia, Xiangjun Xiao, Dirk J. Van Veldhuisen, Alberico L. Catapano, Martin D. Tobin, Alistair S. Hall, Alexandra I.F. Blakemore, Wiek H. Van Gilst, Haidong Zhu, Jeanette Erdmann, Muredach P. Reilly, Sekar Kathiresan, Heribert Schunkert, Philippa J. Talmud, Nancy L. Pedersen, Markus Perola, Willem Ouwehand, Jaakko Kaprio, Nicholas G. Martin, Cornelia M. Van Duijn, Iiris Hovatta, Christian Gieger, Andres Metspalu, Dorret I. Boomsma, Marjo Riitta Jarvelin, P. Eline Slagboom, John R. Thompson, Tim D. Spector, Pim Van Der Harst, Nilesh J. Samani^*

^*Korrespondierende/r Autor/-in für diese Arbeit

824 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Nature Genetics
Jahrgang	45
Ausgabenummer	4
Seiten (von - bis)	422-427
Seitenumfang	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2528
Publikationsstatus	Veröffentlicht - 01.04.2013

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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. 39Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. 40Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 41Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK. 42Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. 43Department of Medical Genetics, University of Helsinki and the Helsinki University Hospital, Helsinki, Finland. 44Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany. 45Munich Heart Alliance, Munich, Germany. 46National Institute for Health and Welfare, Oulu, Finland. 47Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany. 48Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians Universität, Munich, Germany. 49KlinikumGrosshadern, Munich, Germany. 50Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA. 51Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 52Instituto di Ricovero e Cura a Carattere Scientifico Multimedica, Milan, Italy. 53A full list of members is provided in the supplementary Note. 54UniversitätzuLübeck, Medizinische Klinik II, Lübeck, Germany. 55The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 56Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. 57Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. 58Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. 59Department of Hematology, University of Cambridge, Cambridge, UK. 60National Health Service Blood and Transplant, Cambridge, UK. 61University of Helsinki, Hjelt Institute, Department of Public Health, Helsinki, Finland. 62Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland. 63Institute of Health Sciences, University of Oulu, Oulu, Finland. 64Biocenter Oulu, University of Oulu, Oulu, Finland. 65Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland. 66Department of Genetics, University of Groningen, University Medical Center, Groningen, The Netherlands. 67These authors contributed equally to this work. Correspondence should be addressed to N.J.S. ([email protected]).

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10.1038/ng.2528

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Codd, V., Nelson, C. P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J. L., Hottenga, J. J., Fischer, K., Esko, T., Surakka, I., Broer, L., Nyholt, D. R., Leach, I. M., Salo, P., Hägg, S., Matthews, M. K., Palmen, J., Norata, G. D., O'Reilly, P. F., ... Samani, N. J. (2013). Identification of seven loci affecting mean telomere length and their association with disease. Nature Genetics, 45(4), 422-427. https://doi.org/10.1038/ng.2528

@article{81fca4c60d1f4a3f9fb3adbe96a2cf94,

title = "Identification of seven loci affecting mean telomere length and their association with disease",

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.",

author = "Veryan Codd and Nelson, \{Christopher P.\} and Eva Albrecht and Massimo Mangino and Joris Deelen and Buxton, \{Jessica L.\} and Hottenga, \{Jouke Jan\} and Krista Fischer and T{\~o}nu Esko and Ida Surakka and Linda Broer and Nyholt, \{Dale R.\} and Leach, \{Irene Mateo\} and Perttu Salo and Sara H{\"a}gg and Matthews, \{Mary K.\} and Jutta Palmen and Norata, \{Giuseppe D.\} and O'Reilly, \{Paul F.\} and Danish Saleheen and Najaf Amin and Balmforth, \{Anthony J.\} and Marian Beekman and \{De Boer\}, \{Rudolf A.\} and Stefan B{\"o}hringer and Braund, \{Peter S.\} and Burton, \{Paul R.\} and Craen, \{Anton J.Mde\} and Matthew Denniff and Yanbin Dong and Konstantinos Douroudis and Elena Dubinina and Eriksson, \{Johan G.\} and Katia Garlaschelli and Dehuang Guo and Hartikainen, \{Anna Liisa\} and Henders, \{Anjali K.\} and Houwing-Duistermaat, \{Jeanine J.\} and Laura Kananen and Karssen, \{Lennart C.\} and Johannes Kettunen and Norman Klopp and Vasiliki Lagou and \{Van Leeuwen\}, \{Elisabeth M.\} and Madden, \{Pamela A.\} and Reedik M{\"a}gi and Magnusson, \{Patrik K.E.\} and Satu M{\"a}nnist{\"o} and McCarthy, \{Mark I.\} and Medland, \{Sarah E.\} and Evelin Mihailov and Montgomery, \{Grant W.\} and Oostra, \{Ben A.\} and Aarno Palotie and Annette Peters and Helen Pollard and Anneli Pouta and Inga Prokopenko and Samuli Ripatti and Veikko Salomaa and Suchiman, \{H. Eka D.\} and Valdes, \{Ana M.\} and Niek Verweij and Ana Vi{\~n}uela and Xiaoling Wang and Wichmann, \{H. Erich\} and Elisabeth Widen and Gonneke Willemsen and Wright, \{Margaret J.\} and Kai Xia and Xiangjun Xiao and \{Van Veldhuisen\}, \{Dirk J.\} and Catapano, \{Alberico L.\} and Tobin, \{Martin D.\} and Hall, \{Alistair S.\} and Blakemore, \{Alexandra I.F.\} and \{Van Gilst\}, \{Wiek H.\} and Haidong Zhu and Jeanette Erdmann and Reilly, \{Muredach P.\} and Sekar Kathiresan and Heribert Schunkert and Talmud, \{Philippa J.\} and Pedersen, \{Nancy L.\} and Markus Perola and Willem Ouwehand and Jaakko Kaprio and Martin, \{Nicholas G.\} and \{Van Duijn\}, \{Cornelia M.\} and Iiris Hovatta and Christian Gieger and Andres Metspalu and Boomsma, \{Dorret I.\} and Jarvelin, \{Marjo Riitta\} and Slagboom, \{P. Eline\} and Thompson, \{John R.\} and Spector, \{Tim D.\} and \{Van Der Harst\}, Pim and Samani, \{Nilesh J.\}",

year = "2013",

month = apr,

day = "1",

doi = "10.1038/ng.2528",

language = "English",

volume = "45",

pages = "422--427",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "4",

}

Codd, V, Nelson, CP, Albrecht, E, Mangino, M, Deelen, J, Buxton, JL, Hottenga, JJ, Fischer, K, Esko, T, Surakka, I, Broer, L, Nyholt, DR, Leach, IM, Salo, P, Hägg, S, Matthews, MK, Palmen, J, Norata, GD, O'Reilly, PF, Saleheen, D, Amin, N, Balmforth, AJ, Beekman, M, De Boer, RA, Böhringer, S, Braund, PS, Burton, PR, Craen, AJM, Denniff, M, Dong, Y, Douroudis, K, Dubinina, E, Eriksson, JG, Garlaschelli, K, Guo, D, Hartikainen, AL, Henders, AK, Houwing-Duistermaat, JJ, Kananen, L, Karssen, LC, Kettunen, J, Klopp, N, Lagou, V, Van Leeuwen, EM, Madden, PA, Mägi, R, Magnusson, PKE, Männistö, S, McCarthy, MI, Medland, SE, Mihailov, E, Montgomery, GW, Oostra, BA, Palotie, A, Peters, A, Pollard, H, Pouta, A, Prokopenko, I, Ripatti, S, Salomaa, V, Suchiman, HED, Valdes, AM, Verweij, N, Viñuela, A, Wang, X, Wichmann, HE, Widen, E, Willemsen, G, Wright, MJ, Xia, K, Xiao, X, Van Veldhuisen, DJ, Catapano, AL, Tobin, MD, Hall, AS, Blakemore, AIF, Van Gilst, WH, Zhu, H, Erdmann, J, Reilly, MP, Kathiresan, S, Schunkert, H, Talmud, PJ, Pedersen, NL, Perola, M, Ouwehand, W, Kaprio, J, Martin, NG, Van Duijn, CM, Hovatta, I, Gieger, C, Metspalu, A, Boomsma, DI, Jarvelin, MR, Slagboom, PE, Thompson, JR, Spector, TD, Van Der Harst, P & Samani, NJ 2013, 'Identification of seven loci affecting mean telomere length and their association with disease', Nature Genetics, Jg. 45, Nr. 4, S. 422-427. https://doi.org/10.1038/ng.2528

TY - JOUR

T1 - Identification of seven loci affecting mean telomere length and their association with disease

AU - Codd, Veryan

AU - Nelson, Christopher P.

AU - Albrecht, Eva

AU - Mangino, Massimo

AU - Deelen, Joris

AU - Buxton, Jessica L.

AU - Hottenga, Jouke Jan

AU - Fischer, Krista

AU - Esko, Tõnu

AU - Surakka, Ida

AU - Broer, Linda

AU - Nyholt, Dale R.

AU - Leach, Irene Mateo

AU - Salo, Perttu

AU - Hägg, Sara

AU - Matthews, Mary K.

AU - Palmen, Jutta

AU - Norata, Giuseppe D.

AU - O'Reilly, Paul F.

AU - Saleheen, Danish

AU - Amin, Najaf

AU - Balmforth, Anthony J.

AU - Beekman, Marian

AU - De Boer, Rudolf A.

AU - Böhringer, Stefan

AU - Braund, Peter S.

AU - Burton, Paul R.

AU - Craen, Anton J.Mde

AU - Denniff, Matthew

AU - Dong, Yanbin

AU - Douroudis, Konstantinos

AU - Dubinina, Elena

AU - Eriksson, Johan G.

AU - Garlaschelli, Katia

AU - Guo, Dehuang

AU - Hartikainen, Anna Liisa

AU - Henders, Anjali K.

AU - Houwing-Duistermaat, Jeanine J.

AU - Kananen, Laura

AU - Karssen, Lennart C.

AU - Kettunen, Johannes

AU - Klopp, Norman

AU - Lagou, Vasiliki

AU - Van Leeuwen, Elisabeth M.

AU - Madden, Pamela A.

AU - Mägi, Reedik

AU - Magnusson, Patrik K.E.

AU - Männistö, Satu

AU - McCarthy, Mark I.

AU - Medland, Sarah E.

AU - Mihailov, Evelin

AU - Montgomery, Grant W.

AU - Oostra, Ben A.

AU - Palotie, Aarno

AU - Peters, Annette

AU - Pollard, Helen

AU - Pouta, Anneli

AU - Prokopenko, Inga

AU - Ripatti, Samuli

AU - Salomaa, Veikko

AU - Suchiman, H. Eka D.

AU - Valdes, Ana M.

AU - Verweij, Niek

AU - Viñuela, Ana

AU - Wang, Xiaoling

AU - Wichmann, H. Erich

AU - Widen, Elisabeth

AU - Willemsen, Gonneke

AU - Wright, Margaret J.

AU - Xia, Kai

AU - Xiao, Xiangjun

AU - Van Veldhuisen, Dirk J.

AU - Catapano, Alberico L.

AU - Tobin, Martin D.

AU - Hall, Alistair S.

AU - Blakemore, Alexandra I.F.

AU - Van Gilst, Wiek H.

AU - Zhu, Haidong

AU - Erdmann, Jeanette

AU - Reilly, Muredach P.

AU - Kathiresan, Sekar

AU - Schunkert, Heribert

AU - Talmud, Philippa J.

AU - Pedersen, Nancy L.

AU - Perola, Markus

AU - Ouwehand, Willem

AU - Kaprio, Jaakko

AU - Martin, Nicholas G.

AU - Van Duijn, Cornelia M.

AU - Hovatta, Iiris

AU - Gieger, Christian

AU - Metspalu, Andres

AU - Boomsma, Dorret I.

AU - Jarvelin, Marjo Riitta

AU - Slagboom, P. Eline

AU - Thompson, John R.

AU - Spector, Tim D.

AU - Van Der Harst, Pim

AU - Samani, Nilesh J.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84874967142

U2 - 10.1038/ng.2528

DO - 10.1038/ng.2528

M3 - Journal articles

C2 - 23535734

AN - SCOPUS:84874967142

SN - 1061-4036

VL - 45

SP - 422

EP - 427

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

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