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


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.

SUBMITTER: Li C 

PROVIDER: S-EPMC7058826 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Li Chen C   Stoma Svetlana S   Lotta Luca A LA   Warner Sophie S   Albrecht Eva E   Allione Alessandra A   Arp Pascal P PP   Broer Linda L   Buxton Jessica L JL   Da Silva Couto Alves Alexessander A   Deelen Joris J   Fedko Iryna O IO   Gordon Scott D SD   Jiang Tao T   Karlsson Robert R   Kerrison Nicola N   Loe Taylor K TK   Mangino Massimo M   Milaneschi Yuri Y   Miraglio Benjamin B   Pervjakova Natalia N   Russo Alessia A   Surakka Ida I   van der Spek Ashley A   Verhoeven Josine E JE   Amin Najaf N   Beekman Marian M   Blakemore Alexandra I AI   Canzian Federico F   Hamby Stephen E SE   Hottenga Jouke-Jan JJ   Jones Peter D PD   Jousilahti Pekka P   Mägi Reedik R   Medland Sarah E SE   Montgomery Grant W GW   Nyholt Dale R DR   Perola Markus M   Pietiläinen Kirsi H KH   Salomaa Veikko V   Sillanpää Elina E   Suchiman H Eka HE   van Heemst Diana D   Willemsen Gonneke G   Agudo Antonio A   Boeing Heiner H   Boomsma Dorret I DI   Chirlaque Maria-Dolores MD   Fagherazzi Guy G   Ferrari Pietro P   Franks Paul P   Gieger Christian C   Eriksson Johan Gunnar JG   Gunter Marc M   Hägg Sara S   Hovatta Iiris I   Imaz Liher L   Kaprio Jaakko J   Kaaks Rudolf R   Key Timothy T   Krogh Vittorio V   Martin Nicholas G NG   Melander Olle O   Metspalu Andres A   Moreno Concha C   Onland-Moret N Charlotte NC   Nilsson Peter P   Ong Ken K KK   Overvad Kim K   Palli Domenico D   Panico Salvatore S   Pedersen Nancy L NL   Penninx Brenda W J H BWJH   Quirós J Ramón JR   Jarvelin Marjo Riitta MR   Rodríguez-Barranco Miguel M   Scott Robert A RA   Severi Gianluca G   Slagboom P Eline PE   Spector Tim D TD   Tjonneland Anne A   Trichopoulou Antonia A   Tumino Rosario R   Uitterlinden André G AG   van der Schouw Yvonne T YT   van Duijn Cornelia M CM   Weiderpass Elisabete E   Denchi Eros Lazzerini EL   Matullo Giuseppe G   Butterworth Adam S AS   Danesh John J   Samani Nilesh J NJ   Wareham Nicholas J NJ   Nelson Christopher P CP   Langenberg Claudia C   Codd Veryan V  

American journal of human genetics 20200227 3


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  ...[more]

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