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 MiraglioNatalia 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

Research output: Contribution to Journal › Article › Academic › 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
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

Bibliographical note

Funding

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 )[*]. C.P.N is funded by the British Heart Foundation (BHF). V.C., C.P.N., and N.J.S. are supported by the National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Centre and N.J.S. holds an NIHR Senior Investigator award. Chen Li is support by a four-year Wellcome Trust PhD Studentship; C.L., L.A.L., and N.J.W. are funded by the Medical Research Council ( MC_UU_12015/1 ). N.J.W. is an NIHR Senior Investigator. J.D. is funded by the NIHR (Senior Investigator Award).[*]. *The views expressed are those of the authors and not necessarily those of the NHS , the NIHR , or the Department of Health and Social Care. Cohort-specific and further acknowledgments are given in the Supplemental Information . J.D. reports personal fees and non-financial support from Merck Sharpe and Dohme UK Atherosclerosis; personal fees and non-financial support from Novartis Cardiovascular and Metabolic Advisory Board; personal fees and non-financial support from Pfizer Population Research Advisory Panel; and grants from the British Heart Foundation, the European Research Council, Merck, the NIHR, NHS Blood and Transplant, Novartis, Pfizer, the UK Medical Research Council, Health Data Research UK, and the Wellcome Trust outside the submitted work. 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)[*]. C.P.N is funded by the British Heart Foundation (BHF). V.C. C.P.N. and N.J.S. are supported by the National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Centre and N.J.S. holds an NIHR Senior Investigator award. Chen Li is support by a four-year Wellcome Trust PhD Studentship; C.L. L.A.L. and N.J.W. are funded by the Medical Research Council (MC_UU_12015/1). N.J.W. is an NIHR Senior Investigator. J.D. is funded by the NIHR (Senior Investigator Award).[*]. *The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Cohort-specific and further acknowledgments are given in the Supplemental Information.

Funders	Funder number
Cambridge University Hospitals National Health Service
European Commission Framework Programme 7	HEALTH-F2-2012-279233
European Union Framework 7?
European Union Framework 7—Health Theme	HEALTH-F4-2007- 201413
Foundation Trust
Health Data Research UK
Leicester Cardiovascular Biomedical Research Centre
Merck Sharpe and Dohme UK Atherosclerosis
NHS
UK Medical Research Council	MR/L003120/1
National Cancer Institute	ZIABC011815
Merck
Pfizer UK
Wellcome Trust
Medical Research Council	MC_UU_12015/1
National Institute for Health Research
British Heart Foundation	RG/13/13/30194, RG/18/13/33946
European Commission	LSHM-CT-2006-037197
European Research Council

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2020.02.006

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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

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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.",

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

language = "English",

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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, 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 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85080107195&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2020.02.006

DO - 10.1016/j.ajhg.2020.02.006

M3 - Article

C2 - 32109421

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

Abstract

Bibliographical note

Funding

Cohort Studies

UN SDGs

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