Common variants near TERC are associated with mean telomere length
Open accessAbstract
We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 individuals, with follow-up replication in 9,492 individuals. We identified an association with telomere length on 3q26 (rs12696304, combined P = 3.72 x 10(-14)) at a locus that includes TERC, which encodes the telomerase RNA component. Each copy of the minor allele of rs12696304 was associated with an approximately 75-base-pair reduction in mean telomere length, equivalent to approximately 3.6 years of age-related telomere-length attrition.
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CAD risk increased 21% for every standard deviation decrease in LTL.
“CAD risk increased 21% for every standard deviation decrease in LTL, supporting a direct relationship between TL variation and certain age-related diseases like CAD (Codd et al., 2010).”
From Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging (2015) · cites this paper as Codd et al., 2010
Common variants at two loci on Chr3q26 (TERC) and Chr10q24.33 (OBFC1), that explain <1% of the variance in TL, have shown a replicated association with mean LTL in genome-wide association studies.
“So far, common variants at two loci on Chr3q26 (TERC)17–19 and Chr10q24.33 (OBFC1)18, that explain <1% of the variance in TL, have shown a replicated association with mean LTL in genome-wide association (GWA) studies.”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [17]
The most significantly associated locus was the previously reported TERC locus on 3q26.
“The most significantly associated locus we found was the previously reported TERC locus on 3q26 (Figs 1 and 2, Table 1)17.”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [17]
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“Linkage and genome-wide association analysis have identified telomere length associated regions on chromosomes 3, 18, 14, and 10 (Andrew et al., 2006; Codd et al., 2010; Levy et al., 2010; Mangino et al., 2009).”
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“Recent genomewide association analyses of LTL have borne out this prediction [32,33], providing powerful conceptual proof that LTL, and by inferenceHSC telomere length, is an index of telomere length in all leukocytes, despite some variation in telomere length among leukocyte subsets.”
BackgroundGenetics of leukocyte telomere length and its role in atherosclerosis
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“However, because the small (non-significant) effects of the Table 6 Results of gene set analysis of telomere maintenance pathway gene SNP sets Gene PLINK set-based testa Global testa SNP ratio testa ACD 1 0.491 1 DKC1 1 0.642 1 GAR1 1 0.281 1 NHP2 1 0.759 1 NOP10 1 0.208 1 POT1 0.007 0.014 0.019 TEP1 1 0.525 1 TERC 1…”
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“Two recent genome-wide association studies observed association of LTL with two SNPs (rs12696304 and rs3772190) of the TERC locus in individuals of European descent (Codd et al., 2010; Levy et al., 2010).”
BackgroundResultA genetic perspective on coeliac disease
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Sizing the ends: Normal length of human telomeres
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Genome-Wide Association Study of Relative Telomere Length
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“Genome-wide association studies (GWAS) have identified and replicated associations at the TERC locus, which account for no more than 1% of variation in telomere length [51,52].”
BackgroundMethodTelomere Length in Newborns is Related to Maternal Stress During Pregnancy
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“Relative TL was measured using an established quantitative PCR assay (Cawthon, 2002; Codd et al, 2010; Codd et al, 2013).”
MethodInfluentialThe association of telomere length and genetic variation in telomere biology genesa
Mirabello, L. J., Yu, K. F., Kraft, P., Vivo, I. D., Hunter, D. J., Prescott, J., Wong, J. Y. Y., Chatterjee, N., Hayes, R. B., & Savage, S. A. (2010) · Human Mutation · doi:10.1002/humu.21314 · Cited by 109 · see citing works
“The telomerase reverse transcriptase (TERT) and its telomere template-containing RNA component (TERC) are telomere-associated proteins that add telomeric repeats to elongate telomeres [Collins and Mitchell, 2002].”
BackgroundSmall-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells
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“Telomere length is a heritable trait, and a small number of polymorphisms have been associated with telomere length.(13) 14 The hypothesis that shorter telomeres predispose to cancer in the general population initially gained support from an increased risk of cancer in some of the diseases associated with very short t…”
BackgroundResultInfluentialTelomere length in reproduction
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“A common variant near the TERC gene (3q26, rs12696304) was also found in at least two different studies to have a strong association with shorter telomere lengths in leucocytes (Codd et al., 2010; Shen et al., 2011).”
BackgroundWalsh, K. M., Codd, V., Rice, T., Nelson, C. P., Smirnov, I. V., Mccoy, L. S., Hansen, H. M., Elhauge, E., Ojha, J., Francis, S. S., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6468 · Cited by 100 · see citing works
Race, Ethnicity, Psychosocial Factors, and Telomere Length in a Multicenter Setting
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Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer
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“Primers used to amplify telomere repeats and the 36B4 gene were described before [43].”
MethodCirculating leukocyte telomere length and risk of overall and aggressive prostate cancer
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“We identified 32 SNPs from GWA (Rafnar et al, 2009; Codd et al, 2010; Levy et al, 2010; KoteJarai et al, 2011; Prescott et al, 2011; Mangino et al, 2012; Bojesen et al, 2013; Codd et al, 2013; Pooley et al, 2013) or fine mapping studies (Kote-Jarai et al, 2013) that had minor allele frequencies 45%…”
BackgroundInfluentialLeukocyte telomere length and its relation to food and nutrient intake in an elderly population
Tiainen, A.-M., Männistö, S., Blomstedt, P., Moltchanova, E. V., Perälä, M.-M., Kaartinen, N. E., Kajantie, E., Kananen, L., Hovatta, I., & Eriksson, J. G. (2012) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2012.143 · Cited by 92 · see citing works
Mamdani, F., Rollins, B. L., Morgan, L. Z., Myers, R., Barchas, J. D., Schatzberg, A. F., Watson, S. J., Akil, H., Potkin, S. G., Bunney, W. E., et al. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.134 · Cited by 92 · see citing works
Dorajoo, R., Chang, X., Gurung, R. L., Li, Z., Wang, L., Wang, R., Beckman, K. B., Adams‐Haduch, J. M., Yiamunaa, M., Liu, S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10443-2 · Cited by 84 · see citing works
Vascular aging: Molecular mechanisms and potential treatments for vascular rejuvenation
Mistriotis, P., & Andreadis, S. T. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.05.006 · Cited by 88 · see citing works
Telomere length and common disease: study design and analytical challenges
Barrett, J. H., Iles, M. M., Dunning, A. M., & Pooley, K. A. (2015) · Human Genetics · doi:10.1007/s00439-015-1563-4 · Cited by 84 · see citing works
Telomere Length and the Cancer–Atherosclerosis Trade-Off
Stone, R. C., Horvath, K., Kark, J. D., Susser, E., Tishkoff, S. A., & Aviv, A. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006144 · Cited by 82 · see citing works
“, CTC1 and STN1 (OBFC1), telomerase ribonucleoprotein nuclear assembly factor 1 (NAF1), and telomere length maintenance gene regulator of telomere helicase 1 (RTEL1) [7,41,42,44].”
BackgroundTaub, M. A., Conomos, M. P., Keener, R., Iyer, K. R., Weinstock, J. S., Yanek, L. R., Lane, J., Miller‐Fleming, T. W., Brody, J. A., Raffield, L. M., et al. (2022) · Cell Genomics · doi:10.1016/j.xgen.2021.100084 · Cited by 82 · see citing works
Telomere maintenance and the etiology of adult glioma
Walsh, K. M., Wiencke, J. K., Lachance, D. H., Wiemels, J. L., Molinaro, A. M., Eckel‐Passow, J. E., Jenkins, R. B., & Wrensch, M. (2015) · Neuro-Oncology · doi:10.1093/neuonc/nov082 · Cited by 81 · see citing works
Göhring, J., Fulcher, N., Jacak, J., & Říha, K. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1315 · Cited by 80 · see citing works
Heritability of telomere length in a study of long-lived families
Honig, L. S., Kang, M. S., Cheng, R., Eckfeldt, J. H., Thyagarajan, B., Leiendecker‐Foster, C., Province, M. A., Sanders, J. L., Perls, T. T., Christensen, K., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.06.017 · Cited by 79 · see citing works
“Recent genome-wide linkage and association studies have reported candidate loci and gene SNPs (Andrew et al., 2006 ; Codd et al., 2010 ; Deelen et al., 2011 ; Soerensen et al., 2012 ; Vasa-Nicotera et al., 2005).”
BackgroundLeukocyte Telomere Length in the Finnish Diabetes Prevention Study
Hovatta, I., de Mello, V. D., Kananen, L., Lindström, J., Eriksson, J. G., Ilanne‐Parikka, P., Keinanen-Kiukaanniemi, S. M., Peltonen, M., Tuomilehto, J. O., & Uusitupa, M. I. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034948 · Cited by 79 · see citing works
Physical Activity and Telomere Biology: Exploring the Link with Aging-Related Disease Prevention
Ludlow, A. T., & Roth, S. M. (2011) · Journal of Aging Research · doi:10.4061/2011/790378 · Cited by 79 · see citing works
“Beyond aging, shortened telomeres are implicated in genetic syndromes such as dyskeratosis congenita [19, 20], Werner syndromes [21, 22], and aplastic anemia [23].”
BackgroundInherited genetic susceptibility to multiple myeloma
Morgan, G. J., Johnson, D. C., Weinhold, N., Goldschmidt, H., Landgren, O., Lynch, H. T., Hemminki, K., & Houlston, R. S. (2013) · Leukemia · doi:10.1038/leu.2013.344 · Cited by 77 · see citing works
Gu, J. H., Chen, M., Shete, S. S., Amos, C. I., Kamat, A. M., Ye, Y., Lin, J. M., Dinney, C. P., & Wu, X. (2011) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-11-0063 · Cited by 73 · see citing works
Mamdani, F., Rollins, B. L., Morgan, L. Z., Myers, R., Barchas, J. D., Schatzberg, A. F., Watson, S. J., Akil, H., Potkin, S. G., Bunney, W. E., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2015.164 · Cited by 76 · see citing works
Aging, telomeres and heart failure
Wong, L. S. M., van der Harst, P., de Boer, R. A., Huzen, J., van Gilst, W. H., & van Veldhuisen, D. J. (2010) · Heart Failure Reviews · doi:10.1007/s10741-010-9173-7 · Cited by 74 · see citing works
“Genome-wide scans have mapped loci associated with telomere length on chromosome 12[36], 14[37], 18[38] and 3 near TERC (component of the enzyme telomerase) [39].”
BackgroundTelomere Length and Risk of Stroke in Chinese
Ding, H., Chen, C., Shaffer, J. R., Liu, L., Xu, Y., Wang, X., Hui, R., & Wang, D. W. (2012) · Stroke · doi:10.1161/strokeaha.111.637207 · Cited by 73 · see citing works
Telomere Length and the Risk of Alzheimer’s Disease: The Rotterdam Study
Fani, L., Hilal, S., Sedaghat, S., Broer, L., Licher, S., Arp, P., van Meurs, J. B. J., Ikram, M. K., & Ikram, M. A. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190759 · Cited by 72 · see citing works
“Ct values and PCR efficiencies were calculated per plate using the MINER algorithm [15].”
Lee, J. H., Cheng, R., Honig, L. S., Feitosa, M. F., Kammerer, C. M., Kang, M. S., Schupf, N., Lin, S. J., Sanders, J. L., Bae, H. T., et al. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2013.00310 · Cited by 66 · see citing works
Aviv, A., & Susser, E. (2013) · International Journal of Epidemiology · doi:10.1093/ije/dys236 · Cited by 70 · see citing works
Walsh, K. M., Whitehead, T. P., de Smith, A. J., Smirnov, I. V., Park, M., Endicott, A. A., Francis, S. S., Codd, V., Samani, N. J., Metayer, C., et al. (2016) · Carcinogenesis · doi:10.1093/carcin/bgw037 · Cited by 68 · see citing works
Kozlitina, J., & Garcia, C. K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051046 · Cited by 68 · see citing works
Telomere length determinants in childhood
Gorenjak, V., Petrelis, A. M., Stathopoulou, M. G., & Visvikis‐Siest, S. (2019) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2019-0235 · Cited by 69 · see citing works
Shen, Q., Zhang, Z., Yu, L., Cao, L., Zhou, D., Kan, M., Li, B., Zhang, D., He, L., & Liu, Y. (2011) · European Journal of Human Genetics · doi:10.1038/ejhg.2011.4 · Cited by 65 · see citing works
“A recent genome-wide association study (GWAS) identified association of common variants near TERC (on 3q26) with telomere length in two large European cohorts of 2917 individuals, followed by replication in three further European cohorts of 9492 individuals”
Backgroundh TERT Cancer Risk Genotypes Are Associated With Telomere Length
Melin, B. S., Nordfjäll, K., Andersson, U., & Roos, G. (2012) · Genetic Epidemiology · doi:10.1002/gepi.21630 · Cited by 64 · see citing works
A Prospective Study of Leukocyte Telomere Length and Risk of Type 2 Diabetes in Postmenopausal Women
You, N. Y., Chen, B. H., Song, Y., Lu, X., Chen, Y., Manson, J. E., Kang, M., Howard, B. V., Margolis, K. L., Curb, J. D., et al. (2012) · Diabetes · doi:10.2337/db12-0241 · Cited by 64 · see citing works
No association between mean telomere length and life stress observed in a 30 year birth cohort
Jodczyk, S., Fergusson, D. M., Horwood, L. J., Pearson, J. F., & Kennedy, M. A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097102 · Cited by 62 · see citing works
Ladwig, K., Brockhaus, A. C., Baumert, J., Lukaschek, K., Emeny, R. T., Kruse, J., Codd, V., Häfner, S., Albrecht, E., Illig, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064762 · Cited by 63 · see citing works
Epigenetic inheritance of telomere length in wild birds
Bauch, C., Boonekamp, J. J., Korsten, P., Mulder, G., & Verhulst, S. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1007827 · Cited by 62 · see citing works
“Subsequently, during development of the embryo, different telomere maintenance and restoration processes, under the control of different genes, regulate TL (12-16).”
BackgroundTelomeres, Atherosclerosis, and Human Longevity
Aviv, A., Kark, J. D., & Susser, E. (2015) · Epidemiology · doi:10.1097/ede.0000000000000280 · Cited by 61 · see citing works
Biomarkers of aging associated with past treatments in breast cancer survivors
Scuric, Z., Carroll, J., Bower, J. E., Ramos-Perlberg, S., Petersen, L., Esquivel, S., Hogan, M., Chapman, A. M., Irwin, M. R., Breen, E. C., et al. (2017) · npj Breast Cancer · doi:10.1038/s41523-017-0050-6 · Cited by 61 · see citing works
Burke, L. S., Hyland, P. L., Pfeiffer, R. M., Prescott, J., Wheeler, W., Mirabello, L. J., Savage, S. A., Burdette, L. A., Yeager, M., Chanock, S. J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071121 · Cited by 59 · see citing works
Erdem, J. S., Notø, H. Ø., Skare, Ø., Lie, J.-A. S., Petersen‐Øverleir, M., Reszka, E., Pepłońska, B., & Zienolddiny, S. (2017) · Cancer Medicine · doi:10.1002/cam4.1135 · Cited by 58 · see citing works
Saxena, R., Bjonnes, A., Prescott, J., Dib, P. S., Natt, P., Lane, J. M., Lerner, M. R., Cooper, J. A., Ye, Y., Li, K., et al. (2014) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.113.000412 · Cited by 57 · see citing works
Variability in newborn telomere length is explained by inheritance and intrauterine environment
Chen, L., Tan, K. M. L., Gong, M., Chong, M. F., Tan, K. H., Chong, Y. S., Meaney, M. J., Gluckman, P. D., Eriksson, J. G., & Karnani, N. (2022) · BMC Medicine · doi:10.1186/s12916-021-02217-9 · Cited by 57 · see citing works
“2 genomic region has previously been reported to be associated with TL in adults [18, 19].”
BackgroundA Genome-Wide Association Study Identifies a Locus on TERT for Mean Telomere Length in Han Chinese
Liu, Y., Cao, L., Li, Z., Zhou, D., Liu, W., Shen, Q., Wu, Y., Zhang, D., Hu, X., Wang, T., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085043 · Cited by 52 · see citing works
“TERC only accounts for no more than 1% of variation in telomere length [15,16].”
BackgroundResultAssociation Between Left Ventricular Mass and Telomere Length in a Population Study
Kuznetsova, T., Codd, V., Brouilette, S., Thijs, L., González, A., Jin, Y., Richart, T., van der Harst, P., Dı́ez, J., Staessen, J. A., et al. (2010) · American Journal of Epidemiology · doi:10.1093/aje/kwq142 · Cited by 54 · see citing works
The TERT variant rs2736100 is associated with colorectal cancer risk
The Colon Cancer Family Registry, Kinnersley, B., Migliorini, G., Broderick, P., Whiffin, N., Dobbins, S. E., Casey, G., Hopper, J. L., Sieber, O. M., Lipton, L. R., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.329 · Cited by 53 · see citing works
Shorter telomere length in peripheral blood leukocytes is associated with childhood autism
Li, Z., Tang, J., Li, H., Chen, S., Hé, Y., Liao, Y., Wei, Z., Wan, G., Xiang, X., Xia, K., et al. (2014) · Scientific Reports · doi:10.1038/srep07073 · Cited by 53 · see citing works
García-Calzón, S., Martínez‐González, M. Á., Razquín, C., Corella, D., Salas‐Salvadó, J., Martínez, J. A., Zalba, G., & Martí, A. (2014) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.114.000635 · Cited by 55 · see citing works
Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk
Rachakonda, P. S., Kong, H.-Y., Srinivas, N., García‐Casado, Z., Requena, C., Fallah, M., Heidenreich, B., Planelles, D., Traves, V., Schadendorf, D., et al. (2018) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22669 · Cited by 50 · see citing works
Longer leukocyte telomere length in Costa Rica's Nicoya Peninsula: A population-based study
Rehkopf, D. H., Dow, W. H., Rosero‐Bixby, L., Lin, J., Epel, E. S., & Blackburn, E. H. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.08.005 · Cited by 51 · see citing works
Telomere length, genetic variants and gastric cancer risk in a Chinese population
Du, J., Zhu, X., Xie, C.-W., Dai, N., Gu, Y., Zhu, M., Wang, C., Gao, Y., Pan, F., Ren, C., et al. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv075 · Cited by 50 · see citing works
- Authors
- Wellcome Trust Case Control Consortium, Codd, V., Mangino, M., van der Harst, P., Braund, P. S., Kaiser, M., Beveridge, A. J., Rafelt, S., Moore, J., Nelson, C., Soranzo, N., Zhai, G., Valdes, A. M., Blackburn, H., Leach, I. M., de Boer, R. A., Kimura, M., Aviv, A., Goodall, A. H., Ouwehand, W., van Veldhuisen, D. J., van Gilst, W. H., Navis, G., Burton, P. R., Tobin, M. D., Hall, A. S., Thompson, J. R., Spector, T., & Samani, N. J.
- Affiliations
- University of Leicester (GB)
- King's College London (GB)
- Wellcome Sanger Institute (GB)
- University Medical Center Groningen (NL)
- Rutgers New Jersey Medical School (US)
- University of Cambridge (GB)
- University of Leeds (GB)
- Corresponding author
- Samani, Nilesh J
- ORCID
- Venue
- Nature Genetics
- Published
- 2010-02-07
- Volume
- 42
- Issue
- 3
- Pages
- 197-199
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3773906
- OpenAlex
- W1979833091
- Cited by
- 344
- References
- 16
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 14 · 2023: 14 · 2022: 18 · 2021: 23 · 2020: 27 · 2019: 18 · 2018: 11 · 2017: 18 · 2016: 29 · 2015: 30 · 2014: 25 · 2013: 30 · 2012: 33
- FWCI
- 22.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Wellcome Trust (091746)
- British Heart Foundation
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (916.76.170)
- Biotechnology and Biological Sciences Research Council (G20234)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- telomere length, TERC, telomerase RNA, 3q26, leukocyte telomere length, genetic variants, telomere shortening, aging
- MeSH terms
- Age Factors, Aging, Chromosomes, Human, Pair 3, Gene Frequency, Humans, RNA, Time Factors, Meta-Analysis as Topic, Cohort Studies, Telomere, Telomerase, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study
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