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

doi:10.1038/ng.2528

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

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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)	422-7, 427e1-2
Journal	Nature Genetics
Volume	45
Issue number	4
DOIs	https://doi.org/10.1038/ng.2528
Publication status	Published - Apr 2013
Externally published	Yes

Keywords

Biomarkers, Tumor/genetics
Case-Control Studies
Disease/genetics
Female
Genetic Loci/genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Leukocytes/metabolism
Male
Meta-Analysis as Topic
Risk Factors
Telomerase/genetics
Telomere/genetics

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10.1038/ng.2528

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@article{eb88b72de3944ca88f7eb0e9be5a175c,

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.",

keywords = "Biomarkers, Tumor/genetics, Case-Control Studies, Disease/genetics, Female, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Leukocytes/metabolism, Male, Meta-Analysis as Topic, Risk Factors, Telomerase/genetics, Telomere/genetics",

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 {Mateo Leach}, Irene 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 {de Craen}, {Anton J M} and Matthew Denniff and Yanbin Dong and Konstantinos Douroudis and Elena Dubinina and Eriksson, {Johan G} and Katia Garlaschelli and Dehuang Guo and Anna-Liisa Hartikainen 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 {van der Harst}, Pim",

year = "2013",

month = apr,

doi = "10.1038/ng.2528",

language = "English",

volume = "45",

pages = "422--7, 427e1--2",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

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 - Mateo Leach, Irene

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 - de Craen, Anton J M

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 - van der Harst, Pim

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.

KW - Biomarkers, Tumor/genetics

KW - Case-Control Studies

KW - Disease/genetics

KW - Female

KW - Genetic Loci/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Leukocytes/metabolism

KW - Male

KW - Meta-Analysis as Topic

KW - Risk Factors

KW - Telomerase/genetics

KW - Telomere/genetics

U2 - 10.1038/ng.2528

DO - 10.1038/ng.2528

M3 - Article

C2 - 23535734

SN - 1061-4036

VL - 45

SP - 422-7, 427e1-2

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

Abstract

Keywords

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