Polygenic basis and biomedical consequences of telomere length variation.

Genome, Human Genome-Wide Association Study Humans Mendelian Randomization Analysis Multifactorial Inheritance / genetics Quantitative Trait Loci Telomere Homeostasis / genetics

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
10 2021
Historique:
received: 21 03 2021
accepted: 18 08 2021
entrez: 6 10 2021
pubmed: 7 10 2021
medline: 10 11 2021
Statut: ppublish

Résumé

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

Identifiants

DOI: 10.1038/s41588-021-00944-6 PMID: 34611362 PMC: PMC8492471
pubmed: 34611362
doi: 10.1038/s41588-021-00944-6
pii: 10.1038/s41588-021-00944-6
pmc: PMC8492471
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1425-1433

Subventions

Organisme : Medical Research Council
ID : MR/L003120/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/13/13/30194
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M012816/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/12/2/29428
Pays : United Kingdom
Organisme : Medical Research Council
ID : R/L003120/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/18/13/33946
Pays : United Kingdom
Organisme : British Heart Foundation
ID : SP/16/4/32697
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : K08 HG010155
Pays : United States
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom

Informations de copyright

© 2021. The Author(s).

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Auteurs

Veryan Codd (V)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. vc15@le.ac.uk.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. vc15@le.ac.uk.
ORCID: 0000-0002-9430-8254

Qingning Wang (Q)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

Elias Allara (E)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
ORCID: 0000-0002-1634-8330

Crispin Musicha (C)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

Stephen Kaptoge (S)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.

Svetlana Stoma (S)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Tao Jiang (T)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Stephen E Hamby (SE)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

Peter S Braund (PS)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
ORCID: 0000-0001-8540-5709

Vasiliki Bountziouka (V)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

Charley A Budgeon (CA)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia.

Matthew Denniff (M)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Chloe Swinfield (C)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Manolo Papakonstantinou (M)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
ORCID: 0000-0003-2664-9046

Shilpi Sheth (S)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Dominika E Nanus (DE)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Sophie C Warner (SC)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Minxian Wang (M)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-3753-508X

Amit V Khera (AV)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0001-6535-5839

James Eales (J)

Division of Cardiovascular Sciences, University of Manchester, Manchester, UK.
ORCID: 0000-0001-6238-5952

Willem H Ouwehand (WH)

British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
Department of Haematology, University of Cambridge, Cambridge, UK.
NHS Blood and Transplant, Cambridge, UK.
University College London Hospitals NHS Foundation Trust, London, UK.
ORCID: 0000-0002-7744-1790

John R Thompson (JR)

Department of Health Sciences, University of Leicester, Leicester, UK.
ORCID: 0000-0003-4819-1611

Emanuele Di Angelantonio (E)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
Health Data Research UK Cambridge, Wellcome Sanger Institute, EMBL-European Bioinformatics Institute and University of Cambridge, Cambridge, UK.

Angela M Wood (AM)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
Health Data Research UK Cambridge, Wellcome Sanger Institute, EMBL-European Bioinformatics Institute and University of Cambridge, Cambridge, UK.
The Alan Turing Institute, London, UK.

Adam S Butterworth (AS)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
Health Data Research UK Cambridge, Wellcome Sanger Institute, EMBL-European Bioinformatics Institute and University of Cambridge, Cambridge, UK.
ORCID: 0000-0002-6915-9015

John N Danesh (JN)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
Health Data Research UK Cambridge, Wellcome Sanger Institute, EMBL-European Bioinformatics Institute and University of Cambridge, Cambridge, UK.
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK.

Christopher P Nelson (CP)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

Nilesh J Samani (NJ)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. njs@le.ac.uk.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. njs@le.ac.uk.
ORCID: 0000-0002-3286-8133

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questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Génome humain › Polygenic basis and biomedical consequences of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Polygenic basis and biomedical consequences of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Polygenic basis and biomedical consequences of...
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