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Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Li, Chen, Stoma, Svetlana, Lotta, Luca A., Warner, Sophie, Albrecht, Eva, Allione, Alessandra, Arp, Pascal P., Broer, Linda, Bruxton, Jessica L., Alves, Alexessander Da Silva Couto , Deelen, Joris, Fedko, Iryna O., Gordon, Scott D., Jiang, Tao, Karlsson, Robert, Kerrison, Nicola, Loe, Taylor K., Mangino, Massimo, Milaneschi, Yuri, Miraglio, Benjamin, Pervjakova, Natalia, Russo, Alessia, Surakka, Ida, van der Spek, Ashley, Verhoeven, Josine E., Amin, Najaf, Beekman, Marian, Blakemore, Alexandra I., Canzian, Frederico, Hamby, Stephen E., Hottenga, Jouke-Jan, Jones, Peter D., Jousilahti, Pekka, Magi, Reedik, Medland, Sarah E., Montgomery, Grant W., Nyholt, Dale R., Perola, Markus, Pietilainen, Kirsi H., Salomaa, Veikko, Sillanpaa, Elina, Suchiman, H. Eka, van Heemst, Diana, Willemsen, Gonneke, Agudo, Antonio, Boeing, Heiner, Boomsma, Dorret I., Chirlaque, Maria-Dolores, Fagherazzi, Guy, Ferrari, Pietro, Franks, Paul, Gieger, Christian, Eriksson, Johan Gunnar, Gunter, Marc, Hagg, Sara, Hovatta, Iiris, Imaz, Liher, Kaprio, Jaakko, Kaaks, Rudolf and Key, Timothy (2020) Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length American Journal of Human Genetics, 106 (3). pp. 389-404.

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Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Li, Chen
Stoma, Svetlana
Lotta, Luca A.
Warner, Sophie
Albrecht, Eva
Allione, Alessandra
Arp, Pascal P.
Broer, Linda
Bruxton, Jessica L.
Alves, Alexessander Da Silva Couto
Deelen, Joris
Fedko, Iryna O.
Gordon, Scott D.
Jiang, Taot.jiang@surrey.ac.uk
Karlsson, Robert
Kerrison, Nicola
Loe, Taylor K.
Mangino, Massimo
Milaneschi, Yuri
Miraglio, Benjamin
Pervjakova, Natalia
Russo, Alessia
Surakka, Ida
van der Spek, Ashley
Verhoeven, Josine E.
Amin, Najaf
Beekman, Marian
Blakemore, Alexandra I.
Canzian, Frederico
Hamby, Stephen E.
Hottenga, Jouke-Jan
Jones, Peter D.
Jousilahti, Pekka
Magi, Reedik
Medland, Sarah E.
Montgomery, Grant W.
Nyholt, Dale R.
Perola, Markus
Pietilainen, Kirsi H.
Salomaa, Veikko
Sillanpaa, Elina
Suchiman, H. Eka
van Heemst, Diana
Willemsen, Gonneke
Agudo, Antonio
Boeing, Heiner
Boomsma, Dorret I.
Chirlaque, Maria-Dolores
Fagherazzi, Guy
Ferrari, Pietro
Franks, Paul
Gieger, Christian
Eriksson, Johan Gunnar
Gunter, Marc
Hagg, Sara
Hovatta, Iiris
Imaz, Liher
Kaprio, Jaakko
Kaaks, Rudolf
Key, Timothy
Date : 27 February 2020
DOI : 10.1016/j.ajhg.2020.02.006
Copyright Disclaimer : © 2020 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Depositing User : James Marshall
Date Deposited : 09 Mar 2020 14:16
Last Modified : 09 Mar 2020 14:16
URI: http://epubs.surrey.ac.uk/id/eprint/853886

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