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Cited by 933Telomeres, Telomerase, and SenescenceGenetic Associations and EpidemiologyGenetics, Aging, and Longevity in Model Organisms

Identification of seven loci affecting mean telomere length and their association with disease

Open access
CARDIoGRAM consortium, Codd, Veryan, Nelson, Christopher P, Albrecht, Eva, Mangino, Massimo, Deelen, Joris, Buxton, Jessica L, Hottenga, Jouke Jan +92 more·2013·Nature Genetics
DOI 10.1038/ng.2528PMC PMC4006270
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Abstract

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10−8). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5–35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

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Written from the paper’s full text.

TL;DR

A genome-wide meta-analysis in 37,684 individuals plus replication in 10,739 identified seven loci, including five novel loci, associated with mean leukocyte telomere length. A genetic risk score combining all seven loci showed that alleles associated with shorter telomere length were associated with increased coronary artery disease risk.

Key findings

  • Seven loci reached genome-wide significance (\(P<5\times10^{-8}\)) for mean leukocyte telomere length, including five novel loci; five contain genes known in telomere biology: *TERC*, *TERT*, *NAF1*, *OBFC1*, and *RTEL1*.
  • Lead SNPs at *TERC* and *TERT* associate with several cancers and other diseases, including idiopathic pulmonary fibrosis; alleles associated with both shorter and longer telomeres showed associations with specific cancers.
  • In 22,233 coronary artery disease cases and 64,762 controls, a genetic risk score using all seven loci showed that alleles associated with shorter telomere length were associated with increased CAD risk: 21% (95% CI 5–35%) per standard deviation in telomere length, \(p=0.014\).
  • Per-allele effects were equivalent to 1.9–3.9 years of age-related attrition in T/S ratio, estimated as roughly 57–117 bp based on prior Southern blot attrition of about 30 bp per year.

Methods

  • Discovery genome-wide meta-analysis of 37,684 individuals from 15 cohorts, with replication of selected variants in 10,739 individuals from 6 additional cohorts; all subjects were of European descent.
  • Mean leukocyte telomere length was measured by quantitative PCR as a T/S ratio, standardized within cohort by Z-transformation, and analyzed by linear regression adjusted for age, sex, and study-specific covariates; meta-analysis used inverse-variance weighting across 2,362,330 SNPs with genomic control correction.
  • Follow-up analyses included replication of two borderline loci, sex-stratified and conditional association analyses, bioinformatics annotation, telomerase activity assays in 208 individuals, and a genetic risk score analysis in CARDIoGRAM.

Limitations

  • The paper states that the qPCR method cannot directly calculate effects on telomere length in base pairs, so bp estimates rely on prior Southern blot attrition estimates; the telomerase activity analysis had only 80% power to detect a SNP effect explaining 3.7% of variance, so smaller effects may have been missed.
  • The paper notes that the lead SNP at *RTEL1* lies 94 kb from the gene, that bioinformatics cannot exclude other genes in each region, and that CAD genetic risk score interpretation requires caution because variants may have other biological effects, including the *NAF1* locus trending in the opposite direction.
  • Evident from the text: all participants were of European descent, limiting generalizability; replication was limited to selected variants and two borderline loci; and individual CAD SNP associations were not significant, with the CAD finding driven by the combined score.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/ng.2528

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 53 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In a genetic risk score analysis combining lead variants at all seven LTL-associated loci in 22,233 CAD cases and 64,762 controls, alleles associated with shorter LTL were associated with increased risk of CAD (21% (95% CI: 5-35%) per standard deviation in LTL, p=0.014).

    “Moreover, a genetic risk score analysis combining lead variants at all seven loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of CAD (21% (95% CI: 5–35%) per standard deviation in LTL, p=0.014).”
    • Also stated in: § Abstract · plain
      “the combined GRS analysis showed a significant association (p = 0.014) of the allele associated with shorter LTL with increased risk of CAD (Fig 3). Shorter mean LTL equivalent to one SD in LTL was associated with a 21% (95% CI 5% –35%) higher risk of CAD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30] Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–338 (2011). source

      Not checked in the free run.

    • cites [31] International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103–109 (2011). source

      Not checked in the free run.

    • Rests on an assumption: The LTL-associated genetic variants used in the genetic risk score analysis are not associated with CAD through pathways independent of LTL (no horizontal pleiotropy).
    • Rests on an assumption: The genetic variants used in the risk score analysis are randomly assigned at conception and therefore not confounded by environmental factors.
  • Findingcitation

    Five of the seven identified LTL-associated loci contain genes (TERC, TERT, NAF1, OBFC1, RTEL1) known to be involved in telomere biology.

    “Five of the loci contain genes (TERC, TERT, NAF1, OBFC1, RTEL1) that are known to be involved in telomere biology.”
    • Also stated in: § Abstract · plain
      “In addition to this, four further loci – 5p15.33 (TERT), 4q32.2 (NAF1, nuclear assembly factor 1), 10q24.33 (OBFC1, oligonucleotide/oligosaccharide-binding fold containing 1)18 and 20q13.3 (RTEL1, regulator of telomere elongation helicase 1) - harbour genes that encode proteins with known function in telomere biology3, 20–23.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [3] Wang, C. & Meier, U.T. Architecture and assembly of mammalian H/ACA small nucleolar and telomerase ribonucleoproteins. EMBO J. 23, 1857–1867 (2004). source

      Not checked in the free run.

    • cites [20] Egan, E.D. & Collins, K. An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. Mol. Cell. Biol. 32, 2428–2439 (2012). source

      Not checked in the free run.

    • cites [21] Miyake, Y. et al. RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol. Cell 36, 193–206 (2009). source

      Not checked in the free run.

    • cites [22] Ding, H. et al. Regulation of murine telomere length by Rtel1: an essential gene encoding a helicase-like protein. Cell 117, 873–886 (2004). source

      Not checked in the free run.

    • cites [23] Barber, L.J. et al. RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135, 261–271 (2008). source

      Not checked in the free run.

  • Findingcitation

    Lead SNPs at the TERC and TERT loci associate with several cancers and other diseases, including idiopathic pulmonary fibrosis.

    “Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis.”
    • Also stated in: § Abstract · plain
      “The rs10936599 (TERC) allele associated with longer LTL associates with increased risk of colorectal cancer19 and with two autoimmune diseases, multiple sclerosis (longer LTL allele) and celiac disease (shorter LTL allele). The lead SNP for the 5p15.33 (TERT) locus is associated with different cancer types (both shorter and longer LTL alleles) and with increased risk of idiopathic pulmonary fibros”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Jones, A.M. et al. Terc polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. Gut 61, 248–254 (2012). source

      Not checked in the free run.

    • cites [26] Alder, J.K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 105, 13051–13056 (2008). source

      Not checked in the free run.

  • Findingown data

    The previously reported OBFC1 locus was replicated.

    “We also replicated the previously reported OBFC1 locus18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Levy, D. et al. Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc. Natl. Acad. Sci. USA 107, 9293–9298 (2010). source

      Not checked in the free run.

  • Findingown data

    Shorter mean LTL equivalent to one SD in LTL was associated with a 21% (95% CI 5% -35%) higher risk of CAD.

    “Shorter mean LTL equivalent to one SD in LTL was associated with a 21% (95% CI 5% –35%) higher risk of CAD.”
    Quote in the paperSubstantial claim
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    We identified seven loci, including five novel loci, associated with mean LTL at genome-wide significance (P<5x10−8) in a GWAS meta-analysis of 37,684 individuals with replication in 10,739 individuals.

    “Here, in a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in a further 10,739 individuals, we identified seven loci, including five novel loci, associated with mean LTL (P<5x10−8).”
    • Also stated in: § Abstract · plain
      “SNPs in 7 loci showed association with mean LTL at genome-wide significance (P<5x10−8, Fig 1, Table 1, Fig 2 and Supplementary Fig 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Here, we report five novel and confirm two previously reported loci that associate with mean LTL in humans.

    “Here, we report five novel and confirm two previously reported loci that associate with mean LTL in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The association of rs11125529 at 2p16.2 was confirmed in replication, while rs2967374 at 16q23.3 was not.

    “We confirmed the association of rs11125529 but not of rs2967374 (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The rs10936599 (TERC) allele associated with longer LTL associates with increased risk of colorectal cancer and with multiple sclerosis (longer LTL allele) and celiac disease (shorter LTL allele).

    “The rs10936599 (TERC) allele associated with longer LTL associates with increased risk of colorectal cancer19 and with two autoimmune diseases, multiple sclerosis (longer LTL allele) and celiac disease (shorter LTL allele).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Jones, A.M. et al. Terc polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. Gut 61, 248–254 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Although individual lead SNPs were not significantly associated with CAD, 6 out of 7 variants showed consistency in direction and the combined GRS analysis showed a significant association (p = 0.014) of the allele associated with shorter LTL with increased risk of CAD.

    “Although the results for individuals variants were not significant, 6 out of 7 variants showed consistency in direction and the combined GRS analysis showed a significant association (p = 0.014) of the allele associated with shorter LTL with increased risk of CAD (Fig 3).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    The remaining two loci (19p21 and 2p16.2) do not harbour obvious candidate genes related to telomere biology.

    “The remaining two loci (19p21 and 2p16.2) do not harbour obvious candidate genes related to telomere biology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The lead SNP for the 5p15.33 (TERT) locus is associated with different cancer types (both shorter and longer LTL alleles) and with increased risk of idiopathic pulmonary fibrosis (shorter LTL allele).

    “The lead SNP for the 5p15.33 (TERT) locus is associated with different cancer types (both shorter and longer LTL alleles) and with increased risk of idiopathic pulmonary fibrosis (shorter LTL allele), a disease that has previously been shown to be associated with shorter LTL26.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Alder, J.K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 105, 13051–13056 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    There was no evidence of sex-dependent effects or additional independent signals at any of the identified loci.

    “There was no evidence of sex-dependent effects or additional independent signals at any of these loci (Online Methods, Supplementary Tables 3 and 4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    The lead SNP at the RTEL1 locus lies 94 kb from RTEL1.

    “However, it should be noted that the lead SNP lies 94 kb from RTEL1.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In cross-sectional population studies, mean LTL is longer in women than in men and is inversely associated with age, declining by between 20-40 base pairs per year.

    “In cross-sectional population studies mean LTL is longer in women than in men and is inversely associated with age (declining by between 20–40 base-pairs (bp) per year)9, 12–14.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Vasa Nicotera, M. et al. Mapping of a major locus that determines telomere length in humans. Am. J. Hum. Genet. 76, 147–151 (2005). source

      Not checked in the free run.

    • cites [12] Brouilette, S., Singh, R.K., Thompson, J.R., Goodall, A.H. & Samani, N.J. White cell telomere length and risk of premature myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 23, 842–846 (2003). source

      Not checked in the free run.

    • cites [13] Brouilette, S. 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. Heart 94, 422–425 (2008). source

      Not checked in the free run.

    • cites [14] Fitzpatrick, A.L. et al. Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am. J. Epidemiol. 165, 14–21 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mean TL shows considerable inter-individual variability and has high heritability with estimates varying between 44-80%.

    “Mean TL shows considerable inter-individual variability and has high heritability with estimates varying between 44–80%7–9.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Slagboom, P.E., Droog, S. & Boomsma, D.I. Genetic determination of telomere size in humans: a twin study of three age groups. Am. J. Hum. Genet. 55, 876–882 (1994).

      Not checked in the free run.

    • cites [8] Njajou, O.T. et al. Telomere length is paternally inherited and is associated with parental lifespan. Proc. Natl. Acad. Sci. USA 104, 12135–12139 (2007). source

      Not checked in the free run.

    • cites [9] Vasa Nicotera, M. et al. Mapping of a major locus that determines telomere length in humans. Am. J. Hum. Genet. 76, 147–151 (2005). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Because LTL is also affected by other risk factors for CAD such as oxidative stress, it has been unclear whether the association of shorter LTL with CAD is primary or secondary.

    “Because LTL is also affected by other risk factors for CAD such as oxidative stress27–29, it has been unclear whether the association of shorter LTL with CAD is primary or secondary.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Richter, T. & von Zglinicki, T. Continuous correlation between oxidative stress and telomere length shortening in fibroblasts. Exp. Gerontol. 41, 1039–1042 (2007). source

      Not checked in the free run.

    • cites [28] Valdes, A.M. et al. Obesity, cigarette smoking, and telomere length in women. Lancet 366, 662–664 (2005). source

      Not checked in the free run.

    • cites [29] Bekaert, S. et al. Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease. Aging Cell 6, 639–647 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The telomerase activity study had only 80% power (α of 0.05) to detect a SNP effect that explained 3.7% of the variance in telomerase activity, so smaller effects are likely to have been missed.

    “However, the study only had 80% power (α of 0.05) to detect a SNP effect that explained 3.7% of the variance in telomerase activity and therefore smaller effects are likely to have been missed in this exploratory analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The most persuasive evidence for a causal role comes from in vitro and in vivo manipulation of telomerase activity which impacts on TL and has been shown to enhance or reverse senescence and ageing-associated phenotypes.

    “The most persuasive evidence for a causal role comes from in vitro and in vivo manipulation of telomerase activity which impacts on TL and has been shown to enhance or reverse senescence and ageing-associated phenotypes35–39.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [35] Minamino, T. et al. Endothelial cell senescence inhuman atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002). source

      Not checked in the free run.

    • cites [36] Oh, H. et al. Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. Proc. Natl. Acad. Sci. USA 98, 10308–10313 (2001). source

      Not checked in the free run.

    • cites [37] Wong, K.K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003). source

      Not checked in the free run.

    • cites [38] Samper, E., Flores, J.M. & Blasco, M.A. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep. 2, 800–807 (2001). source

      Not checked in the free run.

    • cites [39] Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice. Nature 469, 102–106 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Although strong candidate genes are located in some of the loci, at this stage we cannot overlook the potential involvement of other genes within each region.

    “These findings emphasise that although strong candidate genes are located in some of the loci, at this stage we cannot overlook the potential involvement of other genes within each region.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The extent to which the association of shorter LTL with age-related disorders is causal in nature remains unclear.

    “However, the extent to which the association of shorter LTL with age-related disorders is causal in nature remains unclear.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Because the variants at each of the loci could have other biological effects that could impact on their association with CAD through LTL, some caution is required in the interpretation of this association.

    “Because the variants at each of the loci could have other biological effects that could impact on their association with CAD through LTL (and possibly explain why the NAF1 locus may be trending in the opposite direction), some caution is required in the interpretation of this association.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The findings provide a framework for a genetic approach to investigating the causal role of telomere length in ageing-related diseases.

    “The findings provide a framework for a genetic approach to investigating the causal role of telomere length in ageing-related diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Some of the genetic variants associated with LTL are also associated with risk of specific cancers as well as other diseases, suggesting a causal link.

    “Here, we show that some of the genetic variants associated with LTL are also associated with risk of specific cancers as well as other diseases some of which have been shown to be previously associated with shorter LTL, suggesting a causal link.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Alleles associated with both shorter and longer telomeres showed associations with specific cancers, suggesting that variation in LTL in either direction may contribute to the development of specific cancers.

    “An interesting finding was that alleles associated with both shorter and longer telomeres showed associations with specific cancers suggesting that variation in LTL in either direction may contribute to the development of specific cancers.”
    Quote in the paperSubstantial claim
20 of 20

  • The paper relies on this without support.

    The LTL-associated genetic variants used in the genetic risk score analysis are not associated with CAD through pathways independent of LTL (no horizontal pleiotropy).

    “Because the variants at each of the loci could have other biological effects that could impact on their association with CAD through LTL (and possibly explain why the NAF1 locus may be trending in the opposite direction), some caution is required in the interpretation of this association.”

  • The paper relies on this without support.

    The genetic variants used in the risk score analysis are randomly assigned at conception and therefore not confounded by environmental factors.

    “To investigate whether the association could be causal, we examined the association of both individual lead SNPs and a genetic risk score (GRS) based on a combination of all seven SNPs, (adjusted for their effect size) with CAD in the CARDIoGRAM GWAS meta-analysis comprising 22,233 CAD cases and 64,762 controls of European descent30, using the approach recently described by the ICBP Consortium31.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The finding that cardiovascular disease risk is influenced by common variations in genes known molecularly to act in telomere maintenance and protection supports a causal role for impaired telomere maintenance in partially contributing to cardiovascular disease.

    “Because this large meta-analysis showed that the risk of cardiovascular disease is influenced by common variations in a defined set of genes known molecularly to act specifically in telomere maintenance and protection (Codd et al., 2013), this finding supports a causal role for impaired telomere maintenance in partially contributing to cardiovascular disease.”

    From Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging (2015) · cites this paper as Codd et al., 2013

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The chromosome 19 locus is assigned two different bands

    Minor

    The remaining chromosome 19 locus is called 19p21 in one sentence and 19p12 in the next.

1 of 1

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Authors
CARDIoGRAM consortium, Codd, V., Nelson, C. P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J. L., Hottenga, J. J., Fischer, K., Esko, T., Surakka, I., Broer, L., Nyholt, D. R., Leach, I. M., Salo, P., Hägg, S., Matthews, M. K., Palmen, J., Norata, G. D., O'Reilly, P. F., Saleheen, D., Amin, N., Balmforth, A. J., Beekman, M., de Boer, R. A., Böhringer, S., Braund, P. S., Burton, P. R., Craen, A. J. M., Denniff, M., Dong, Y., Douroudis, K., Dubinina, E., Eriksson, J. G., Garlaschelli, K., Guo, D., Hartikainen, A.-L., Henders, A. K., Houwing-Duistermaat, J. J., Kananen, L., Karssen, L. C., Kettunen, J., Klopp, N., Lagou, V., van Leeuwen, E. M., Madden, P. A., Mägi, R., Magnusson, P. K. E., Männistö, S., McCarthy, M. I., Medland, S. E., Mihailov, E., Montgomery, G. W., Oostra, B. A., Palotie, A., Peters, A., Pollard, H., Pouta, A., Prokopenko, I., Ripatti, S., Salomaa, V., Suchiman, H. E. D., Valdes, A. M., Verweij, N., Viñuela, A., Wang, X., Wichmann, H.-E., Widen, E., Willemsen, G., Wright, M. J., Xia, K., Xiao, X., van Veldhuisen, D. J., Catapano, A. L., Tobin, M. D., Hall, A. S., Blakemore, A. I. F., van Gilst, W. H., Zhu, H., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Talmud, P. J., Pedersen, N. L., Perola, M., Ouwehand, W., Kaprio, J., Martin, N. G., van Duijn, C. M., Hovatta, I., Gieger, C., Metspalu, A., Boomsma, D. I., Jarvelin, M.-R., Slagboom, P. E., Thompson, J. R., Spector, T. D., van der Harst, P., & Samani, N. J.
Affiliations
  • University of Leicester (GB)
  • Helmholtz Munich (DE)
  • King's College London (GB)
  • Leiden University Medical Center (NL)
  • Imperial College London (GB)
  • Vrije Universiteit Amsterdam (NL)
  • University of Tartu (EE)
  • University of Helsinki (FI)
  • QIMR Berghofer Medical Research Institute (AU)
  • University Medical Center Groningen (NL)
  • Finnish Institute for Health and Welfare (FI)
  • Karolinska Institutet (SE)
  • University College London (GB)
  • Queen Mary University of London (GB)
  • University of Cambridge (GB)
  • Erasmus MC (NL)
  • University of Leeds (GB)
  • Ospedale Bassini (IT)
  • University of Oulu (FI)
  • University of Oxford (GB)
  • Washington University in St. Louis (US)
  • Centre for Human Genetics (GB)
  • University of North Carolina at Chapel Hill (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • University of Milan (IT)
  • University of Lübeck (DE)
  • University of Pennsylvania (US)
  • Broad Institute (US)
Corresponding author
Samani, Nilesh J
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2013-03-27
Volume
45
Issue
4
Pages
422-427
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.2528
PMC
PMC4006270
OpenAlex
W2024809912
Semantic Scholar
d64aa55d6cc0d39691bca9100e007f06e658e682
Cited by
933
References
53
Citations by year
2026: 18 · 2025: 49 · 2024: 62 · 2023: 56 · 2022: 64 · 2021: 77 · 2020: 82 · 2019: 92 · 2018: 100 · 2017: 82 · 2016: 90 · 2015: 74 · 2014: 56 · 2013: 28 · 2012: 1
FWCI
56.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
  • Explore Bristol Research (publishedVersion)
  • VU Research Portal (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • eSpace (Curtin University) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • Wellcome Trust (090532)
  • National Institute for Health and Care Research (NF-SI-0611-10170)
  • Medical Research Council (MR/K014536/1)
  • National Institute on Drug Abuse (R56DA012854)
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
leukocyte telomere length, TERC, telomerase reverse transcriptase, NAF1, RTEL1, coronary artery disease, cancer risk, idiopathic pulmonary fibrosis, age-related diseases, polygenic risk score, telomere biology
MeSH terms
Disease, Female, Humans, Leukocytes, Male, Risk Factors, Biomarkers, Tumor, Meta-Analysis as Topic, Case-Control Studies, Telomere, Telomerase, Genetic Predisposition to Disease, Genome-Wide Association Study, Genetic Loci

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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