Polygenic basis and biomedical consequences of telomere length variation

Veryan Codd; Qingning Wang; Elias Allara; Crispin Musicha; Stephen Kaptoge; Svetlana Stoma; Tao Jiang; Stephen E Hamby; Peter S Braund; Vasiliki Bountziouka; Charley A Budgeon; Matthew Denniff; Chloe Swinfield; Manolo Papakonstantinou; Shilpi Sheth; Dominika E Nanus; Sophie C Warner; Minxian Wang; Amit V Khera; James Eales; Willem H Ouwehand; John R Thompson; Emanuele Di Angelantonio; Angela M Wood; Adam S Butterworth; John N Danesh; Christopher P Nelson; Nilesh J Samani

doi:10.1038/s41588-021-00944-6

Polygenic basis and biomedical consequences of telomere length variation

Nat Genet. 2021 Oct;53(10):1425-1433. doi: 10.1038/s41588-021-00944-6. Epub 2021 Oct 5.

Authors

Veryan Codd^{1

2}, Qingning Wang^#^{3

4}, Elias Allara^#^{5

6}, Crispin Musicha^#^{3

4}, Stephen Kaptoge^#^{5

6

7}, Svetlana Stoma³, Tao Jiang⁵, Stephen E Hamby^{3

4}, Peter S Braund³, Vasiliki Bountziouka^{3

4}, Charley A Budgeon^{3

4

8}, Matthew Denniff³, Chloe Swinfield³, Manolo Papakonstantinou³, Shilpi Sheth³, Dominika E Nanus³, Sophie C Warner³, Minxian Wang^{9

10}, Amit V Khera^{9

10

11

12}, James Eales¹³, Willem H Ouwehand^{7

14

15

16}, John R Thompson¹⁷, Emanuele Di Angelantonio^{5

6

7

18}, Angela M Wood^{5

6

7

18

19}, Adam S Butterworth^{5

6

7

18}, John N Danesh^{5

6

7

18

20}, Christopher P Nelson^{3

4}, Nilesh J Samani^{21

22}

Affiliations

¹ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. vc15@le.ac.uk.
² NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. vc15@le.ac.uk.
³ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
⁴ NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
⁵ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
⁷ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
⁸ School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia.
⁹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹³ Division of Cardiovascular Sciences, University of Manchester, Manchester, UK.
¹⁴ Department of Haematology, University of Cambridge, Cambridge, UK.
¹⁵ NHS Blood and Transplant, Cambridge, UK.
¹⁶ University College London Hospitals NHS Foundation Trust, London, UK.
¹⁷ Department of Health Sciences, University of Leicester, Leicester, UK.
¹⁸ Health Data Research UK Cambridge, Wellcome Sanger Institute, EMBL-European Bioinformatics Institute and University of Cambridge, Cambridge, UK.
¹⁹ The Alan Turing Institute, London, UK.
²⁰ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
²¹ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. njs@le.ac.uk.
²² NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. njs@le.ac.uk.

^# Contributed equally.

Abstract

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.

Publication types

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

MeSH terms

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

Abstract

Publication types

MeSH terms

Grants and funding