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. 2013 Apr;45(4):422-7, 427e1-2.
doi: 10.1038/ng.2528.

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

Veryan Codd  1 , 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 M de 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; CARDIoGRAM consortium; 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
Affiliations

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

Veryan Codd et al. Nat Genet. 2013 Apr.

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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Figures

Figure 1
Figure 1. Signal intensity plot of genotype association with telomere length
Data is displayed as –log10P values against chromosomal location for the 2,362,330SNPs that were tested. The dotted line represents a genome-wide level of significance at P=5x10−8. The 7 loci that showed an association at this level are plotted in red.
Figure 2
Figure 2. Regional associations plots for the associated loci
For each SNP –log10P is plotted against base pair position for each of the loci (A-G). Regional plots are shown in order of strongest association - Chr3q26 (A), Chr5p15.33 (B), Chr4q32.2 (C), Chr10q24.33 (D), Chr19p12 (E) Chr20q13.3 (F), Chr2p16.2 (G). Within each locus the lead SNP is represented in purple and the LD relationship of other SNPs to this is indicated by the colour as shown in the right hand panel of each plot. Blue peaks represent recombination rates (HapMap 2) and the RefSeq genes within each region are given in the lower panel.
Figure 3
Figure 3. TL variants and risk of CAD
Forest plot showing the effect of telomere length on CAD risk obtained for each SNP using a risk score analysis for each SNP. Effect sizes are plotted with 95% CI intervals. The overall estimate is from a fixed-effects meta-analysis over all SNPs, where the odds ratio relates to the change in CAD risk for a standard deviation change in telomere length.
See this image and copyright information in PMC

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