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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Acknowledgements
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.
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V.C. and N.J.S. supervised the overall study. V.C., M.M., T.D.S., P.v.d.H. and N.J.S. designed the study. M.M., T.E., D.R.N., R.A.d.B., G.D.N., D.S., N.A., A.J.B., P.S.B., P.R.B., K.D., M.D., J.G.E., K.G., A.-L.H., A.K.H., L.C. Karssen, J.K., N.K., V.L., I.M.L., E.M.v.L., P.A.M., R.M., P.K.E.M., S.M., M.I.M., S.E.M., E.M., G.W.M., B.A.O., J.P., A. Palotie, A. Peters, Anneli Pouta, I.P., S.R.,V.S., A.M.V., N.V., A.V., H.-E.W., E.W., G.W., M.J.W., K.X., X.X., D.J.v.V., A.L.C., M.D.T., A.S.H., A.I.F.B., P.J.T., N.L.P., M.P., J.D., W.O., J. Kaprio, N.G.M., C.M.v.D., C.G., A.M., D.I.B., M.-R.J., W.H.v.G., P.E.S., T.D.S., P.v.d.H. and N.J.S. contributed to recruitment, study and data management, genotyping and/or imputation of individual studies. V.C., J.L.B., M.K.M., R.A.d.B., J.P., E.D., L.K., H.P., P.T.J. and I.H. measured telomere length. C.P.N., E.A., M.M., J.D., J.L.B., J.J.H., K.F., T.E., I.S., L.B., D.R.N., R.A.d.B., P.S., S.H., G.D.N., P.F.O., I.M.L., S.E.M. and P.v.d.H. undertook association analysis of individual studies; C.P.N., E.A. and J.R.T. carried out the meta-analysis and the additional reported analyses. H.Z., X.W., D.G. and Y.D. provided data on telomerase activity and genotypes. J.E., M.P.R., S.K. and H.S. contributed CAD association data on behalf of CARDIoGRAM. V.C. and N.J.S. prepared the paper together with C.P.N., E.A., M.M. and P.v.d.H. and all authors reviewed the paper.
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Codd, V., Nelson, C., Albrecht, E. et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet 45, 422–427 (2013). https://doi.org/10.1038/ng.2528
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DOI: https://doi.org/10.1038/ng.2528
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