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

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

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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 language	English
Pages (from-to)	422-427
Number of pages	6
Journal	Nature Genetics
Volume	45
Issue number	4
DOIs	https://doi.org/10.1038/ng.2528
Publication status	Published - Apr 2013
Externally published	Yes

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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., ... Medland, S. E. (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{fd2e409554844ee4b9371b5ffaa0ece2,

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.}",

year = "2013",

month = apr,

doi = "10.1038/ng.2528",

language = "English",

volume = "45",

pages = "422--427",

journal = "Nature Genetics",

issn = "1061-4036",

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 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

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.

PY - 2013/4

Y1 - 2013/4

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 - http://www.scopus.com/inward/record.url?scp=84874967142&partnerID=8YFLogxK

U2 - 10.1038/ng.2528

DO - 10.1038/ng.2528

M3 - Article

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

Abstract

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