Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length

Alexessander Da Silva Couto Alves; Joris Deelen; Iryna O. Fedko; 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; Scott D. Gordon; Tao Jiang; Robert Karlsson; Nicola Kerrison; Linda Broer; Jessica L. Buxton; Chen Li; Pascal P. Arp; Svetlana Stoma; Luca A. Lotta; Sophie Warner; Eva Albrecht; Alessandra Allione

doi:10.1016/j.ajhg.2020.02.006

Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length

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

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

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
Journal	The American Journal of Human Genetics
Volume	106
Issue number	3
Early online date	27 Feb 2020
DOIs	https://doi.org/10.1016/j.ajhg.2020.02.006
Publication status	Published - 5 Mar 2020

Bibliographical note

Note: The ENGAGE Project was funded under the European Union Framework 7—Health Theme (HEALTH-F4-2007- 201413). The InterAct project received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). The EPIC-CVD study was supported by core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust). This work is also supported by the British Heart Foundation (BHF), the National Institute for Health Research (NIHR), Leicester Cardiovascular Biomedical Research Centre, the Wellcome Trust, the Medical Research Council (MC_UU_12015/1).

Keywords

Biological sciences

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10.1016/j.ajhg.2020.02.006

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Da Silva Couto Alves, A., Deelen, J., Fedko, I. O., Loe, T. K., Mangino, M., Milaneschi, Y., Miraglio, B., Pervjakova, N., Russo, A., Surakka, I., van der Spek, A., Verhoeven, J. E., Amin, N., Beekman, M., Blakemore, A. I., Canzian, F., Hamby, S. E., Hottenga, J.-J., Jones, P. D., ... Allione, A. (2020). Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length. The American Journal of Human Genetics, 106(3), 389-404. https://doi.org/10.1016/j.ajhg.2020.02.006

@article{07ed4582b25e45129bf49140df04b861,

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 = "Biological sciences",

author = "\{Da Silva Couto Alves\}, Alexessander and Joris Deelen and Fedko, \{Iryna O.\} 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 Jouke-Jan Hottenga 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 Maria-Dolores Chirlaque 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 and Gordon, \{Scott D.\} and Tao Jiang and Robert Karlsson and Nicola Kerrison and Linda Broer and Buxton, \{Jessica L.\} and Chen Li and Arp, \{Pascal P.\} and Svetlana Stoma and Lotta, \{Luca A.\} and Sophie Warner and Eva Albrecht and Alessandra Allione",

note = "Note: The ENGAGE Project was funded under the European Union Framework 7—Health Theme (HEALTH-F4-2007- 201413). The InterAct project received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). The EPIC-CVD study was supported by core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust). This work is also supported by the British Heart Foundation (BHF), the National Institute for Health Research (NIHR), Leicester Cardiovascular Biomedical Research Centre, the Wellcome Trust, the Medical Research Council (MC\_UU\_12015/1).",

year = "2020",

month = mar,

day = "5",

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

language = "English",

volume = "106",

pages = "389--404",

journal = "The American Journal of Human Genetics",

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number = "3",

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Da Silva Couto Alves, A, Deelen, J, Fedko, IO, 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, J-J, 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, M-D, 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, Gordon, SD, Jiang, T, Karlsson, R, Kerrison, N, Broer, L, Buxton, JL, Li, C, Arp, PP, Stoma, S, Lotta, LA, Warner, S, Albrecht, E & Allione, A 2020, 'Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length', The 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 - Da Silva Couto Alves, Alexessander

AU - Deelen, Joris

AU - Fedko, Iryna O.

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

AU - Gordon, Scott D.

AU - Jiang, Tao

AU - Karlsson, Robert

AU - Kerrison, Nicola

AU - Broer, Linda

AU - Buxton, Jessica L.

AU - Li, Chen

AU - Arp, Pascal P.

AU - Stoma, Svetlana

AU - Lotta, Luca A.

AU - Warner, Sophie

AU - Albrecht, Eva

AU - Allione, Alessandra

N1 - Note: The ENGAGE Project was funded under the European Union Framework 7—Health Theme (HEALTH-F4-2007- 201413). The InterAct project received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). The EPIC-CVD study was supported by core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust). This work is also supported by the British Heart Foundation (BHF), the National Institute for Health Research (NIHR), Leicester Cardiovascular Biomedical Research Centre, the Wellcome Trust, the Medical Research Council (MC_UU_12015/1).

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 - Biological sciences

U2 - 10.1016/j.ajhg.2020.02.006

DO - 10.1016/j.ajhg.2020.02.006

M3 - Article

SN - 0002-9297

VL - 106

SP - 389

EP - 404

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

IS - 3

ER -

Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length

Abstract

Bibliographical note

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