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

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

doi:10.1016/j.ajhg.2020.02.006

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

Chen Li
, Svetlana Stoma
, Luca A. Lotta
, Sophie Warner
, Eva Albrecht
, Alessandra Allione
, Pascal P. Arp
, Linda Broer
, Jessica L. Buxton
, Alexessander Da Silva Couto Alves
, Joris Deelen
, Iryna O. Fedko
, Scott D. Gordon
, Tao Jiang
, Robert Karlsson
, Nicola Kerrison
, Taylor K. Loe
, Massimo Mangino
, Yuri Milaneschi
, Benjamin Miraglio

Natalia Pervjakova, Alessia Russo, Ida Surakka, Ashley van der Spek, Josine E. Verhoeven, Najaf Amin, Marian Beekman, Alexandra I. Blakemore, Federico Canzian, Stephen E. Hamby, Jouke Jan Hottenga, Peter D. Jones, Pekka Jousilahti, Reedik Mägi, Sarah E. Medland, Grant W. Montgomery, Dale R. Nyholt, Markus Perola, Kirsi H. Pietiläinen, Veikko Salomaa, Elina Sillanpää, H. Eka Suchiman, Diana van Heemst, Gonneke Willemsen, Antonio Agudo, Heiner Boeing, Dorret I. Boomsma, Maria Dolores Chirlaque, Guy Fagherazzi, Pietro Ferrari, Paul Franks, Christian Gieger, Johan Gunnar Eriksson, Marc Gunter, Sara Hägg, Iiris Hovatta, Liher Imaz, Jaakko Kaprio, Rudolf Kaaks, Timothy Key, Vittorio Krogh, Nicholas G. Martin, Olle Melander, Andres Metspalu, Concha Moreno, N. Charlotte Onland-Moret, Peter Nilsson, Ken K. Ong, Kim Overvad, Domenico Palli, Salvatore Panico, Nancy L. Pedersen, Brenda W.J.H. Penninx, J. Ramón Quirós, Marjo Riitta Jarvelin, Miguel Rodríguez-Barranco, Robert A. Scott, Gianluca Severi, P. Eline Slagboom, Tim D. Spector, Anne Tjonneland, Antonia Trichopoulou, Rosario Tumino, André G. Uitterlinden, Yvonne T. van der Schouw, Cornelia M. van Duijn, Elisabete Weiderpass, Eros Lazzerini Denchi, Giuseppe Matullo, Adam S. Butterworth, John Danesh, Nilesh J. Samani, Nicholas J. Wareham, Christopher P. Nelson, Claudia Langenberg^*, Veryan Codd

^*Corresponding author for this work

University of Cambridge
University Hospitals of Leicester NHS Trust
University of Leicester
Helmholtz Zentrum München - German Research Center for Environmental Health
University of Turin
Italian Institute for Genomic Medicine
Erasmus University Rotterdam
Kingston University
University College London
Imperial College Healthcare NHS Trust
University of Surrey
Max Planck Institute for Biology of Ageing
Leiden University
Vrije Universiteit Amsterdam
Queensland Institute of Medical Research
Karolinska Institutet
Scripps Research Institute
King's College London
NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust
Amsterdam UMC
University of Helsinki
University of Tartu
University of Michigan, Ann Arbor
Brunel University London
Imperial College London
German Cancer Research Center
National Institute for Health and Welfare
University of Queensland
Queensland University of Technology
Helsinki University Hospital
University of Jyväskylä
Bellvitge Biomedical Research Institute
German Institute of Human Nutrition Potsdam-Rehbruecke
IMIB—Arrixaca
Biomedical Research Networking Center in Epidemiology and Public Health (CiberESP)
Institut Gustave Roussy
Luxembourg Institute of Health
International Agency for Research on Cancer
Lund University
Umeå University
German Center for Diabetes Research
National University of Singapore
Ministry of Health of the Basque Government
Instituto de Investigación Sanitaria Biodonostia
University of Oxford
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
Instituto de Salud Publica, Pamplona
Utrecht University
Aarhus University
Aalborg University
Institute for the Study and Prevention of Cancer
University of Naples Federico II
Consejería de Sanidad
Escuela Andaluza de Salud Publica
Instituto de Investigación Biosanitaria ibs.GRANADA
Renal and Cardiovascular Epidemiology
University of Florence
Danish Cancer Society
Helenic Health Foundation
Provincial Health Authority (ASP)
No Profit Organization
National Institutes of Health
Cambridge University Hospitals NHS Foundation Trust
Wellcome Trust Sanger Institute

Research output: Contribution to journal › Article › peer-review

134 Citations (Scopus)

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.

Original language	English
Pages (from-to)	389-404
Number of pages	16
Journal	American Journal of Human Genetics
Volume	106
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2020.02.006
Publication status	Published - 5 Mar 2020
Externally published	Yes

Keywords

Mendelian randomisation
age-related disease
biological aging
telomere length

Access to Document

10.1016/j.ajhg.2020.02.006

Cite this

Li, C., Stoma, S., Lotta, L. A., Warner, S., Albrecht, E., Allione, A., Arp, P. P., Broer, L., Buxton, J. L., Da Silva Couto Alves, A., Deelen, J., Fedko, I. O., Gordon, S. D., Jiang, T., Karlsson, R., Kerrison, N., Loe, T. K., Mangino, M., Milaneschi, Y., ... Codd, V. (2020). Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length. American Journal of Human Genetics, 106(3), 389-404. https://doi.org/10.1016/j.ajhg.2020.02.006

@article{2c54e1f24078464193043e714999017f,

title = "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.",

keywords = "Mendelian randomisation, age-related disease, biological aging, telomere length",

author = "Chen Li and Svetlana Stoma and Lotta, \{Luca A.\} and Sophie Warner and Eva Albrecht and Alessandra Allione and Arp, \{Pascal P.\} and Linda Broer and Buxton, \{Jessica L.\} and \{Da Silva Couto Alves\}, Alexessander and Joris Deelen and Fedko, \{Iryna O.\} and Gordon, \{Scott D.\} and Tao Jiang and Robert Karlsson and Nicola Kerrison and Loe, \{Taylor K.\} and Massimo Mangino and Yuri Milaneschi and Benjamin Miraglio and Natalia Pervjakova and Alessia Russo and Ida Surakka and \{van der Spek\}, Ashley and Verhoeven, \{Josine E.\} and Najaf Amin and Marian Beekman and Blakemore, \{Alexandra I.\} and Federico Canzian and Hamby, \{Stephen E.\} and Hottenga, \{Jouke Jan\} and Jones, \{Peter D.\} and Pekka Jousilahti and Reedik M{\"a}gi and Medland, \{Sarah E.\} and Montgomery, \{Grant W.\} and Nyholt, \{Dale R.\} and Markus Perola and Pietil{\"a}inen, \{Kirsi H.\} and Veikko Salomaa and Elina Sillanp{\"a}{\"a} and Suchiman, \{H. Eka\} and \{van Heemst\}, Diana and Gonneke Willemsen and Antonio Agudo and Heiner Boeing and Boomsma, \{Dorret I.\} and Chirlaque, \{Maria Dolores\} and Guy Fagherazzi and Pietro Ferrari and Paul Franks and Christian Gieger and Eriksson, \{Johan Gunnar\} and Marc Gunter and Sara H{\"a}gg and Iiris Hovatta and Liher Imaz and Jaakko Kaprio and Rudolf Kaaks and Timothy Key and Vittorio Krogh and Martin, \{Nicholas G.\} and Olle Melander and Andres Metspalu and Concha Moreno and Onland-Moret, \{N. Charlotte\} and Peter Nilsson and Ong, \{Ken K.\} and Kim Overvad and Domenico Palli and Salvatore Panico and Pedersen, \{Nancy L.\} and Penninx, \{Brenda W.J.H.\} and Quir{\'o}s, \{J. Ram{\'o}n\} and Jarvelin, \{Marjo Riitta\} and Miguel Rodr{\'i}guez-Barranco and Scott, \{Robert A.\} and Gianluca Severi and Slagboom, \{P. Eline\} and Spector, \{Tim D.\} and Anne Tjonneland and Antonia Trichopoulou and Rosario Tumino and Uitterlinden, \{Andr{\'e} G.\} and \{van der Schouw\}, \{Yvonne T.\} and \{van Duijn\}, \{Cornelia M.\} and Elisabete Weiderpass and Denchi, \{Eros Lazzerini\} and Giuseppe Matullo and Butterworth, \{Adam S.\} and John Danesh and Samani, \{Nilesh J.\} and Wareham, \{Nicholas J.\} and Nelson, \{Christopher P.\} and Claudia Langenberg and Veryan Codd",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = mar,

day = "5",

doi = "10.1016/j.ajhg.2020.02.006",

language = "English",

volume = "106",

pages = "389--404",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "3",

}

Li, C, Stoma, S, Lotta, LA, Warner, S, Albrecht, E, Allione, A, Arp, PP, Broer, L, Buxton, JL, Da Silva Couto Alves, A, Deelen, J, Fedko, IO, Gordon, SD, Jiang, T, Karlsson, R, Kerrison, N, Loe, TK, Mangino, M, Milaneschi, Y, Miraglio, B, Pervjakova, N, Russo, A, Surakka, I, van der Spek, A, Verhoeven, JE, Amin, N, Beekman, M, Blakemore, AI, Canzian, F, Hamby, SE, Hottenga, JJ, Jones, PD, Jousilahti, P, Mägi, R, Medland, SE, Montgomery, GW, Nyholt, DR, Perola, M, Pietiläinen, KH, Salomaa, V, Sillanpää, E, Suchiman, HE, van Heemst, D, Willemsen, G, Agudo, A, Boeing, H, Boomsma, DI, Chirlaque, MD, Fagherazzi, G, Ferrari, P, Franks, P, Gieger, C, Eriksson, JG, Gunter, M, Hägg, S, Hovatta, I, Imaz, L, Kaprio, J, Kaaks, R, Key, T, Krogh, V, Martin, NG, Melander, O, Metspalu, A, Moreno, C, Onland-Moret, NC, Nilsson, P, Ong, KK, Overvad, K, Palli, D, Panico, S, Pedersen, NL, Penninx, BWJH, Quirós, JR, Jarvelin, MR, Rodríguez-Barranco, M, Scott, RA, Severi, G, Slagboom, PE, Spector, TD, Tjonneland, A, Trichopoulou, A, Tumino, R, Uitterlinden, AG, van der Schouw, YT, van Duijn, CM, Weiderpass, E, Denchi, EL, Matullo, G, Butterworth, AS, Danesh, J, Samani, NJ, Wareham, NJ, Nelson, CP, Langenberg, C & Codd, V 2020, 'Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length', American Journal of Human Genetics, vol. 106, no. 3, pp. 389-404. https://doi.org/10.1016/j.ajhg.2020.02.006

TY - JOUR

T1 - Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

AU - Li, Chen

AU - Stoma, Svetlana

AU - Lotta, Luca A.

AU - Warner, Sophie

AU - Albrecht, Eva

AU - Allione, Alessandra

AU - Arp, Pascal P.

AU - Broer, Linda

AU - Buxton, Jessica L.

AU - Da Silva Couto Alves, Alexessander

AU - Deelen, Joris

AU - Fedko, Iryna O.

AU - Gordon, Scott D.

AU - Jiang, Tao

AU - Karlsson, Robert

AU - Kerrison, Nicola

AU - Loe, Taylor K.

AU - Mangino, Massimo

AU - Milaneschi, Yuri

AU - Miraglio, Benjamin

AU - Pervjakova, Natalia

AU - Russo, Alessia

AU - Surakka, Ida

AU - van der Spek, Ashley

AU - Verhoeven, Josine E.

AU - Amin, Najaf

AU - Beekman, Marian

AU - Blakemore, Alexandra I.

AU - Canzian, Federico

AU - Hamby, Stephen E.

AU - Hottenga, Jouke Jan

AU - Jones, Peter D.

AU - Jousilahti, Pekka

AU - Mägi, Reedik

AU - Medland, Sarah E.

AU - Montgomery, Grant W.

AU - Nyholt, Dale R.

AU - Perola, Markus

AU - Pietiläinen, Kirsi H.

AU - Salomaa, Veikko

AU - Sillanpää, Elina

AU - Suchiman, H. Eka

AU - van Heemst, Diana

AU - Willemsen, Gonneke

AU - Agudo, Antonio

AU - Boeing, Heiner

AU - Boomsma, Dorret I.

AU - Chirlaque, Maria Dolores

AU - Fagherazzi, Guy

AU - Ferrari, Pietro

AU - Franks, Paul

AU - Gieger, Christian

AU - Eriksson, Johan Gunnar

AU - Gunter, Marc

AU - Hägg, Sara

AU - Hovatta, Iiris

AU - Imaz, Liher

AU - Kaprio, Jaakko

AU - Kaaks, Rudolf

AU - Key, Timothy

AU - Krogh, Vittorio

AU - Martin, Nicholas G.

AU - Melander, Olle

AU - Metspalu, Andres

AU - Moreno, Concha

AU - Onland-Moret, N. Charlotte

AU - Nilsson, Peter

AU - Ong, Ken K.

AU - Overvad, Kim

AU - Palli, Domenico

AU - Panico, Salvatore

AU - Pedersen, Nancy L.

AU - Penninx, Brenda W.J.H.

AU - Quirós, J. Ramón

AU - Jarvelin, Marjo Riitta

AU - Rodríguez-Barranco, Miguel

AU - Scott, Robert A.

AU - Severi, Gianluca

AU - Slagboom, P. Eline

AU - Spector, Tim D.

AU - Tjonneland, Anne

AU - Trichopoulou, Antonia

AU - Tumino, Rosario

AU - Uitterlinden, André G.

AU - van der Schouw, Yvonne T.

AU - van Duijn, Cornelia M.

AU - Weiderpass, Elisabete

AU - Denchi, Eros Lazzerini

AU - Matullo, Giuseppe

AU - Butterworth, Adam S.

AU - Danesh, John

AU - Samani, Nilesh J.

AU - Wareham, Nicholas J.

AU - Nelson, Christopher P.

AU - Langenberg, Claudia

AU - Codd, Veryan

PY - 2020/3/5

Y1 - 2020/3/5

N2 - 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.

AB - 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.

KW - Mendelian randomisation

KW - age-related disease

KW - biological aging

KW - telomere length

UR - https://www.scopus.com/pages/publications/85080107195

U2 - 10.1016/j.ajhg.2020.02.006

DO - 10.1016/j.ajhg.2020.02.006

M3 - Article

C2 - 32109421

AN - SCOPUS:85080107195

SN - 0002-9297

VL - 106

SP - 389

EP - 404

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

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

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Keywords

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