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

Research output: Contribution to journalArticle

432 Citations (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.

Original languageEnglish (US)
Pages (from-to)422-427
Number of pages6
JournalNature Genetics
Volume45
Issue number4
DOIs
StatePublished - Apr 1 2013

Fingerprint

Telomere
Leukocytes
Coronary Artery Disease
Idiopathic Pulmonary Fibrosis
Single Nucleotide Polymorphism
Meta-Analysis
Neoplasms
Alleles
Genome
Confidence Intervals
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Codd, V., Nelson, C. P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J. L., ... 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

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

In: Nature Genetics, Vol. 45, No. 4, 01.04.2013, p. 422-427.

Research output: Contribution to journalArticle

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, vol. 45, no. 4, pp. 422-427. https://doi.org/10.1038/ng.2528
Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL et al. Identification of seven loci affecting mean telomere length and their association with disease. Nature Genetics. 2013 Apr 1;45(4):422-427. https://doi.org/10.1038/ng.2528
Codd, Veryan ; Nelson, Christopher P. ; Albrecht, Eva ; Mangino, Massimo ; Deelen, Joris ; Buxton, Jessica L. ; Hottenga, Jouke Jan ; Fischer, Krista ; Esko, Tõnu ; Surakka, Ida ; Broer, Linda ; Nyholt, Dale R. ; Leach, Irene Mateo ; Salo, Perttu ; Hägg, Sara ; Matthews, Mary K. ; Palmen, Jutta ; Norata, Giuseppe D. ; O'Reilly, Paul F. ; Saleheen, Danish ; Amin, Najaf ; Balmforth, Anthony J. ; Beekman, Marian ; De Boer, Rudolf A. ; Böhringer, Stefan ; Braund, Peter S. ; Burton, Paul R. ; Craen, Anton J.Mde ; Denniff, Matthew ; Dong, Yanbin ; Douroudis, Konstantinos ; Dubinina, Elena ; Eriksson, Johan G. ; Garlaschelli, Katia ; Guo, Dehuang ; Hartikainen, Anna Liisa ; Henders, Anjali K. ; Houwing-Duistermaat, Jeanine J. ; Kananen, Laura ; Karssen, Lennart C. ; Kettunen, Johannes ; Klopp, Norman ; Lagou, Vasiliki ; Van Leeuwen, Elisabeth M. ; Madden, Pamela A. ; Mägi, Reedik ; Magnusson, Patrik K.E. ; Männistö, Satu ; McCarthy, Mark I. ; Medland, Sarah E. ; Mihailov, Evelin ; Montgomery, Grant W. ; Oostra, Ben A. ; Palotie, Aarno ; Peters, Annette ; Pollard, Helen ; Pouta, Anneli ; Prokopenko, Inga ; Ripatti, Samuli ; Salomaa, Veikko ; Suchiman, H. Eka D. ; Valdes, Ana M. ; Verweij, Niek ; Viñuela, Ana ; Wang, Xiaoling ; Wichmann, H. Erich ; Widen, Elisabeth ; Willemsen, Gonneke ; Wright, Margaret J. ; Xia, Kai ; Xiao, Xiangjun ; Van Veldhuisen, Dirk J. ; Catapano, Alberico L. ; Tobin, Martin D. ; Hall, Alistair S. ; Blakemore, Alexandra I.F. ; Van Gilst, Wiek H. ; Zhu, Haidong ; Erdmann, Jeanette ; Reilly, Muredach P. ; Kathiresan, Sekar ; Schunkert, Heribert ; Talmud, Philippa J. ; Pedersen, Nancy L. ; Perola, Markus ; Ouwehand, Willem ; Kaprio, Jaakko ; Martin, Nicholas G. ; Van Duijn, Cornelia M. ; Hovatta, Iiris ; Gieger, Christian ; Metspalu, Andres ; Boomsma, Dorret I. ; Jarvelin, Marjo Riitta ; Slagboom, P. Eline ; Thompson, John R. ; Spector, Tim D. ; Van Der Harst, Pim ; Samani, Nilesh J. / Identification of seven loci affecting mean telomere length and their association with disease. In: Nature Genetics. 2013 ; Vol. 45, No. 4. pp. 422-427.
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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.

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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.

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