Identification of seven loci affecting mean telomere length and their association with disease.
Codd V., Nelson CP., Albrecht E., Mangino M., Deelen J., Buxton JL., Hottenga JJ., Fischer K., Esko T., Surakka I., Broer L., Nyholt DR., Mateo Leach I., 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., de Craen AJM., Denniff M., Dong Y., Douroudis K., Dubinina E., Eriksson JG., Garlaschelli K., Guo D., Hartikainen A-L., 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 H-E., 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., CARDIoGRAM consortium None., 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 M-R., Slagboom PE., Thompson JR., Spector TD., van der Harst P., Samani NJ.
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.