학술논문
Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
Document Type
Author
Li, Chen; Stoma, Svetlana; Lotta, Luca A.; Warner, Sophie; Albrecht, Eva; Allione, Alessandra; Arp, Pascal P.; Broer, Linda; Buxton, Jessica L.; Da Silva Couto Alves, Alexessander; 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, Federico; Hamby, Stephen E.; Hottenga, Jouke-Jan; Jones, Peter D.; Jousilahti, Pekka; Mägi, Reedik; Medland, Sarah E.; Montgomery, Grant W.; Nyholt, Dale R.; Perola, Markus; Pietiläinen, Kirsi H.; Salomaa, Veikko; Sillanpää, 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 W.; Gieger, Christian; Eriksson, Johan Gunnar; Gunter, Marc; Hagg, Sara; Hovatta, Iiris; Imaz, Liher; Kaprio, Jaakko; Kaaks, Rudolf; Key, Timothy; Krogh, Vittorio; Martin, Nicholas G.; Melander, Olle; Metspalu, Andres; Moreno, Concha; Onland-Moret, N. Charlotte; Nilsson, Peter; Ong, Ken K.; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Pedersen, Nancy L.; Penninx, Brenda W. J. H.; Quirós, J. Ramón; Riitta Jarvelin, Marjo; Rodríguez-Barranco, Miguel; Scott, Robert A.; Severi, Gianluca; Slagboom, P. Eline; Spector, Tim D.; Tjonneland, Anne; Trichopoulou, Antonia; Tumino, Rosario; Uitterlinden, André G.; van der Schouw, Yvonne T.; van Duijn, Cornelia M.; Weiderpass, Elisabete; Denchi, Eros Lazzerini; Matullo, Giuseppe; Butterworth, Adam S.; Danesh, John; Samani, Nilesh J.; Wareham, Nicholas J.; Nelson, Christopher P.; Langenberg, Claudia; Codd, Veryan
Source
American Journal of Human Genetics. 106(3):389-404
Subject
Language
English
ISSN
0002-9297
1537-6605
1537-6605
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.