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.

• author: Li, Chen ; Perola, Markus ; Franks, Paul ; Eriksson, Johan Gunnar ; Melander, Olle ; Nilsson, Peter and Codd, Veryan
• author collaboration: ENGAGE consortium
• organization: Genetic and Molecular Epidemiology (research group); EXODIAB: Excellence of Diabetes Research in Sweden; EpiHealth: Epidemiology for Health; Cardiovascular Research - Hypertension (research group)
• publishing date: 2020
• type: Contribution to journal
• publication status: published
• subject: Medical Genetics
• keywords: age-related disease, biological aging, Mendelian randomisation, telomere length
• in: American Journal of Human Genetics
• volume: 106
• issue: 3
• pages: 389 - 404
• publisher: Cell Press
• external identifiers: pmid:32109421; scopus:85080107195
• ISSN: 0002-9297
• DOI: 10.1016/j.ajhg.2020.02.006
• language: English
• LU publication?: yes
• additional info: Funding Information: 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 . Funding 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. Funding Information: 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. Publisher Copyright: © 2020 The Author(s) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
• id: 11710ffd-da84-4326-be0b-382b4af208ad
• date added to LUP: 2021-02-24 11:10:16
• date last changed: 2024-06-14 10:15:16