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Nature genetics
10, 2021;53 (10): 1425-1433.

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
Author Information
  1. Veryan Codd: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. vc15@le.ac.uk. ORCID
  2. Qingning Wang: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  3. Elias Allara: British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ORCID
  4. Crispin Musicha: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  5. Stephen Kaptoge: British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  6. Svetlana Stoma: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  7. Tao Jiang: British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  8. Stephen E Hamby: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  9. Peter S Braund: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. ORCID
  10. Vasiliki Bountziouka: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  11. Charley A Budgeon: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  12. Matthew Denniff: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  13. Chloe Swinfield: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  14. Manolo Papakonstantinou: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. ORCID
  15. Shilpi Sheth: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  16. Dominika E Nanus: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  17. Sophie C Warner: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  18. Minxian Wang: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  19. Amit V Khera: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  20. James Eales: Division of Cardiovascular Sciences, University of Manchester, Manchester, UK. ORCID
  21. Willem H Ouwehand: British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK. ORCID
  22. John R Thompson: Department of Health Sciences, University of Leicester, Leicester, UK. ORCID
  23. Emanuele Di Angelantonio: British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  24. Angela M Wood: British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  25. Adam S Butterworth: British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ORCID
  26. John N Danesh: British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  27. Christopher P Nelson: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  28. Nilesh J Samani: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. njs@le.ac.uk. ORCID
PMID: 34611362 DOI: 10.1038/s41588-021-00944-6

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.

References

  1. Chan, S. W. R. L. & Blackburn, E. H. Telomeres and telomerase. Philos. Trans. R. Soc. B 359, 109–121 (2004). [DOI: 10.1098/rstb.2003.1370]
  2. Broer, L. et al. Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect. Eur. J. Hum. Genet. 21, 1163–1110 (2013). [PMID: 23321625]
  3. Li, C. et al. Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length. Am. J. Hum. Genet. 106, 389–404 (2020). [PMID: 32109421]
  4. Dorajoo, R. et al. Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies. Nat. Commun. 10, 2491 (2019). [PMID: 31171785]
  5. Armanios, M. & Blackburn, E. H. The telomere syndromes. Nat. Rev. Genet. 13, 693–704 (2012). [PMID: 22965356]
  6. Wentzensen, I. M., Mirabello, L., Pfeiffer, R. M. & Savage, S. A. The association of telomere length and cancer: a meta-analysis. Cancer Epidemiol. Biomark. Prev. 20, 1238–1250 (2011). [DOI: 10.1158/1055-9965.EPI-11-0005]
  7. Brouilette, S. W. et al. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet 369, 107–114 (2007). [PMID: 17223473]
  8. Valdes, A. M. et al. Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos. Int. 18, 1203–1210 (2007). [PMID: 17347788]
  9. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013). [PMID: 23746838]
  10. Samani, N. J. & van der Harst, P. Biological ageing and cardiovascular disease. Heart 94, 537–539 (2008). [PMID: 18411343]
  11. Haycock, P. C. et al. Association between telomere length and risk of cancer and non-neoplastic diseases. JAMA Oncol. 3, 636–651 (2017). [PMID: 28241208]
  12. Aviv, A. & Shay, J. W. Reflections on telomere dynamics and ageing-related diseases in humans. Philos. Trans. R. Soc. B 373, 20160436 (2018). [DOI: 10.1098/rstb.2016.0436]
  13. Demanelis, K. et al. Determinants of telomere length across human tissues. Science 369, eaaz6876 (2020). [PMID: 32913074]
  14. Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018). [PMID: 30305743]
  15. Codd, V. et al. A major population resource to investigate determinants and biomedical consequences of leucocyte telomere length. Preprint at medRxiv https://doi.org/doi:10.1101/2021.03.18.21253457 (2021).
  16. Xu, C. et al. Estimating genome-wide significance for whole-genome sequencing studies. Genet. Epidemiol. 38, 281–290 (2014). [PMID: 24676807]
  17. Mangino, M. et al. Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. Hum. Mol. Genet. 21, 5385–5394 (2012). [PMID: 23001564]
  18. Lim, C. J. & Cech, T. R. Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization. Nat. Rev. Mol. Cell Biol. 22, 283–298 (2021). [PMID: 33564154]
  19. Sobinoff, A. P. & Picket, H. A. Alternative lengthening of telomeres: DNA repair pathways converge. Trends Genet. 33, 921–932 (2017). [PMID: 28969871]
  20. Episkopou, H. et al. TSPYL5 depletion induces specific death of ALT cells through USP7-dependent proteasomal degradation of POT1. Mol. Cell 75, 469–482 (2019). [PMID: 31278054]
  21. Grozdanov, P. N., Roy, S., Kittur, N. & Meier, U. T. SHQ1 is required prior to NAF1 for assembly of H/ACA small nucleolar and telomerase RNPs. RNA 15, 1188–1197 (2009). [PMID: 19383767]
  22. Redon, S., Reichenbach, P. & Lingner, J. Protein–RNA and protein–protein interactions mediate association of human EST1A/SMG6 with telomerase. Nucleic Acids Res. 35, 7011–7022 (2007). [PMID: 17940095]
  23. Venteicher, A. S., Meng, Z., Mason, M. J., Veenstra, T. D. & Artandi, S. E. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell 132, 945–957 (2008). [PMID: 18358808]
  24. Bizarro, J., Bhardwaj, A., Smith, S. & Meier, U. T. Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length. Mol. Biol. Cell 30, 3136–3150 (2019). [PMID: 31664887]
  25. Tseng, C. et al. Human telomerase RNA processing and quality control. Cell Rep. 13, 2232–2243 (2015). [PMID: 26628367]
  26. Chen, L. et al. An activity switch in human telomerase based on RNA conformation and shaped by TCAB1. Cell 174, 218–230 (2018). [PMID: 29804836]
  27. Chen, L. et al. Loss of human TGS1 hypermethylase promotes increased telomerase RNA and telomere elongation. Cell Rep. 30, 1358–1372 (2020). [PMID: 32023455]
  28. Kroustallaki, P. et al. SMUG1 promotes telomere maintenance through telomerase RNA processing. Cell Rep. 28, 1690–1702 (2019). [PMID: 31412240]
  29. Arnoult, N. & Karlseder, J. Complex interactions between the DNA-damage response and mammalian telomeres. Nat. Struct. Mol. Biol. 22, 859–866 (2015). [PMID: 26581520]
  30. Dueva, R. & Iliakis, G. Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond. NAR Cancer 2, zcaa022 (2020). [PMID: 34316690]
  31. Sui, J. et al. DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication. Nucleic Acids Res. 43, 5971–5983 (2015). [PMID: 25999341]
  32. Sarkar, J. et al. SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nucleic Acids Res. 43, 5912–5923 (2015). [PMID: 25990736]
  33. Majerska, J., Feretzaki, M., Glousker, G. & Lingner, J. Transformation-induced stress at telomeres is counteracted through changes in the telomeric proteome including SAMHD1. Life Sci. Alliance 1, e201800121 (2018). [PMID: 30456372]
  34. Garcia-Exposito, L. et al. Proteomic profiling reveals a specific role for translesion DNA polymerase η in the alternative lengthening of telomeres. Cell Rep. 17, 1858–1871 (2016). [PMID: 27829156]
  35. Awad, A. et al. Full length RTEL1 is required for the elongation of the single-stranded telomeric overhang by telomerase. Nucleic Acids Res. 48, 7239–7251 (2020). [PMID: 32542379]
  36. Demanelis, K., Tong, L. & Pierce, B. L. Genetically increased telomere length and aging-related traits in the U.K. Biobank. J. Gerontol. A 76, 15–22 (2021). [DOI: 10.1093/gerona/glz240]
  37. Rodriguez-Fraticelli, A. E. et al. Clonal analysis of lineage fate in native haematopoiesis. Nature 553, 212–216 (2018). [PMID: 29323290]
  38. Astle, W. J. et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell 167, 1415–1429 (2016). [PMID: 27863252]
  39. Choudry, F. A. et al. Transcriptional characterization of human megakaryocyte polyploidization and lineage commitment. J. Thromb. Haemost. 19, 1236–1249 (2021). [PMID: 33587817]
  40. Brown, D. W. et al. Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes. PLoS Genet. 16, e1009078 (2020). [PMID: 33090998]
  41. Barthel, F. P. et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat. Genet. 49, 349–357 (2017). [PMID: 28135248]
  42. Bakaysa, S. L. et al. Telomere length predicts survival independent of genetic influences. Aging Cell 6, 769–774 (2007). [PMID: 17925004]
  43. Deelen, J. et al. Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers. Int. J. Epidemiol. 43, 878–886 (2014). [PMID: 24425829]
  44. Steenstrup, T. et al. Telomeres and the natural lifespan limit in humans. Aging 9, 1130–1142 (2017). [PMID: 28394764]
  45. Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011). [PMID: 21113150]
  46. Farzaneh-Far, R. et al. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA 303, 250–257 (2010). [PMID: 20085953]
  47. Aviv, A., Anderson, J. J. & Shay, J. W. Mutations, cancer and the telomere length paradox. Trends Cancer 3, 253–258 (2017). [PMID: 28718437]
  48. Doll, R., Peto, R., Boreham, J. & Sutherland, I. Mortality in relation to smoking. Brit. Med. J. 328, 1519 (2004). [PMID: 15213107]
  49. Sattar, N. et al. Age at diagnosis of type 2 diabetes mellitus and associations with cardiovascular and mortality risks. Circulation 139, 2228–2237 (2019). [PMID: 30955347]
  50. Simes, R. J. An improved Bonferroni procedure for multiple tests of significance. Biometrika 73, 751–754 (1986). [DOI: 10.1093/biomet/73.3.751]
  51. Zhang, Q., Privé, F., Vilhjálmsson, B. & Speed, D. Improved genetic prediction of complex traits from individual-level data or summary statistics. Nat. Commun. 12, 4192 (2021). [PMID: 34234142]
  52. Benner, C. et al. FINEMAP: efficient variable selection using summary data from genome-wide association studies. Bioinformatics 32, 1493–1501 (2016). [PMID: 26773131]
  53. Hans, D. et al. Shotgun stochastic search for ‘large p’ regression. J. Am. Stat. Assoc. 102, 507–516 (2007). [DOI: 10.1198/016214507000000121]
  54. McLaren, W. et al. The Ensembl Variant Effect Predictor. Genome Biol. 17, 122 (2016). [PMID: 27268795]
  55. Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014). [PMID: 24830394]
  56. GTEx Consortium. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).
  57. Jin, Y. et al. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat. Genet. 48, 1418–1424 (2016). [PMID: 27723757]
  58. Mi, H., Muruganujan, A., Ebert, D., Huang, X. & Thomas, P. D. PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 47, D419–D426 (2019). [PMID: 30407594]
  59. Szustakowski, J. D. et al. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nat. Genet. 53, 942–948 (2020). [DOI: 10.1038/s41588-021-00885-0]
  60. Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). [PMID: 32461654]
  61. Watanabe, K. et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat. Genet. 51, 1339–1348 (2019). [PMID: 31427789]
  62. Minelli, C. et al. The use of two-sample methods for Mendelian randomization analyses on single large datasets. Int. J. Epidemiol. https://doi.org/10.1093/ije/dyab084 (2021).
  63. Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658–665 (2013). [PMID: 24114802]
  64. Bowden, J., Davey Smith, G. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512–525 (2015). [PMID: 26050253]
  65. Bowden, J., Davey Smith, G., Haycock, P. C. & Burgess, S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40, 304–314 (2016). [PMID: 27061298]
  66. Burgess, S. et al. A robust and efficient method for Mendelian randomization with hundreds of genetic variants. Nat. Commun. 11, 376 (2020). [PMID: 31953392]
  67. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies via imputation of genotypes. Nat. Genet. 39, 906–913 (2007). [PMID: 17572673]
  68. White, I. R., Kaptoge, S., Royston, P. & Sauerbrei, W. Meta-analysis of non-linear exposure-outcome relationships using individual participant data: a comparison of two methods. Stat. Med. 38, 326–338 (2019). [PMID: 30284314]
  69. Hsieh, F. Y., Bloch, D. A. & Larsen, M. D. A simple method of sample size calculation for linear and logistic regression. Stat. Med. 17, 1623–1634 (1998). [PMID: 9699234]
  70. Ambler, G. & Royston, P. Fractional polynomial model selection procedures: investigation of type I error rate. J. Stat. Comput. Simul. 69, 89–108 (2001). [DOI: 10.1080/00949650108812083]
  71. The Emerging Risk Factors Collaboration. Association of cardiometabolic multimorbidity with mortality. JAMA 314, 52–60 (2015).

Grants

  1. MR/L003120/1/Medical Research Council
  2. MC_PC_17228/Medical Research Council
  3. RG/13/13/30194/British Heart Foundation
  4. MR/M012816/1/Medical Research Council
  5. CH/12/2/29428/British Heart Foundation
  6. R/L003120/1/Medical Research Council
  7. RG/18/13/33946/British Heart Foundation
  8. SP/16/4/32697/British Heart Foundation
  9. /Biotechnology and Biological Sciences Research Council
  10. K08 HG010155/NHGRI NIH HHS
  11. MC_QA137853/Medical Research Council

MeSH Term

Genome, Human
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Multifactorial Inheritance
Quantitative Trait Loci
Telomere Homeostasis
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 106

Word Cloud

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