Heritability Of Telomere Length Research Articles

Telomere heritability and parental age at conception effects in a wild avian population.

Individual variation in telomere length is predictive of health and mortality risk across a range of species. However, the relative influence of environmental and genetic variation on individual telomere length in wild populations remains poorly understood. Heritability of telomere length has primarily been calculated using parent-offspring regression which can be confounded by shared environments. To control for confounding variables, quantitative genetic "animal models" can be used, but few studies have applied animal models in wild populations. Furthermore, parental age at conception may also influence offspring telomere length, but most studies have been cross-sectional. We investigated within- and between-parental age at conception effects and heritability of telomere length in the Seychelles warbler using measures from birds caught over 20years and a multigenerational pedigree. We found a weak negative within-paternal age at conception effect (as fathers aged, their offspring had shorter telomeres) and a weak positive between-maternal age at conception effect (females that survived to older ages had offspring with longer telomeres). Animal models provided evidence that heritability and evolvability of telomere length were low in this population, and that variation in telomere length was not driven by early-life effects of hatch period or parental identities. Quantitative polymerase chain reaction plate had a large influence on telomere length variation and not accounting for it in the models would have underestimated heritability. Our study illustrates the need to include and account for technical variation in order to accurately estimate heritability, as well as other environmental effects, on telomere length in natural populations.

Epigenetic inheritance of telomere length in wild birds.

Telomere length (TL) predicts health and survival across taxa. Variation in TL between individuals is thought to be largely of genetic origin, but telomere inheritance is unusual, because zygotes already express a TL phenotype, the TL of the parental gametes. Offspring TL changes with paternal age in many species including humans, presumably through age-related TL changes in sperm, suggesting an epigenetic inheritance mechanism. However, present evidence is based on cross-sectional analyses, and age at reproduction is confounded with between-father variation in TL. Furthermore, the quantitative importance of epigenetic TL inheritance is unknown. Using longitudinal data of free-living jackdaws Corvus monedula, we show that erythrocyte TL of subsequent offspring decreases with parental age within individual fathers, but not mothers. By cross-fostering eggs, we confirmed the paternal age effect to be independent of paternal age dependent care. Epigenetic inheritance accounted for a minimum of 34% of the variance in offspring TL that was explained by paternal TL. This is a minimum estimate, because it ignores the epigenetic component in paternal TL variation and sperm TL heterogeneity within ejaculates. Our results indicate an important epigenetic component in the heritability of TL with potential consequences for offspring fitness prospects.

Young parents produce offspring with short telomeres: A study in a long-lived bird, the Black-browed Albatross (Thalassarche melanophrys).

In wild vertebrates, young parents are less likely to successfully rear offspring relative to older ones because of lower parental skills (‘the constraint hypothesis’), lower parental investment (‘the restraint hypothesis’) or because of a progressive disappearance of lower-quality individuals at young ages (‘the selection hypothesis’). Because it is practically difficult to follow an offspring during its entire life, most studies have only focused on the ability of individuals to breed or produce young, while neglecting the ability of such young to subsequently survive and reproduce. Several proxies of individual quality can be useful to assess the ability of young to survive and recruit into the population. Among them, telomere length measurement appears especially promising because telomere length has been linked to longevity and fitness in captive and wild animals. By sampling 51 chicks reared by known-aged parents, we specifically tested whether parental age was correlated to offspring telomere length and body condition in a long-lived bird species, the Black-browed Albatross (Thalassarche melanophrys). Young Black-browed albatrosses produced chicks with shorter telomere relative to those raised by older ones. Short offspring telomeres could result from poor developmental conditions or heritability of telomere length. Moreover, young parents also had chicks of lower body condition when compared with older parents, although this effect was significant in female offspring only. Overall, our study demonstrates that parental age is correlated to two proxies of offspring fitness (body condition and telomere length), suggesting therefore that older individuals provide better parental cares to their offspring because of increased parental investment (restraint hypothesis), better foraging/parental skills (constraint hypothesis) or because only high-quality individuals reach older ages (selection hypothesis).

Heritability of telomere length in a study of long-lived families

Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age-associated processes. Because LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have reported heritability. Here, we use a family-based study of longevity to study heritability of LTL in 3037 individuals. We show that LTL is shorter in older individuals, and in males, and has a high heritability (overall h2 = 0.54). In the offspring generation, who are in middle-life, we find an ordinal relationship: persons more-closely-related to elderly probands have longer LTL than persons less-closely-related, who nonetheless have longer LTL than unrelated spouses of the offspring generation. These results support a prominent genetic underpinning of LTL. Elucidation of such genetic bases may provide avenues for intervening in the aging process.

Telomere length variation reduces with age: evidence of survivor effect

Telomere shortening has been associated with aging and mortality but findings are inconsistent. A reason for inconsistencies may be a reduced variance in telomere length in the elderly: a survivor effect. A previous study attributed this survivor effect to a selection against those with short and with long telomeres. Using a multigenerational design in the Erasmus Rucphen Family (ERF) study we aimed to explore the variability of telomere length in different age-categories. Building upon the high heritability of telomere length, we next used the telomere length of the (grand)children of the oldest-old as a proxy for the telomere length of the oldest-old at younger ages. We found a significant reduction in variance in telomere length from young adulthood to old age (p-value = 4.23*10 -6 ). The decline in telomere length variance was stronger in men (69.9%) compared to women (59.7%). The mean telomere length of the (grand)children of the oldest-old was significantly longer compared to others in the same age-range (p-value = 2.60*10 -4 ). Our study shows a reduction in the variance of telomere length over age. Further our study suggests that those with long telomere length survive longest.

Abstract A85: Paternal age at birth is associated with leukocyte telomere length in the Nurses' Health Study

Abstract Despite the high heritability of telomere length, genome-wide association studies have not found common genetic variants with a strong influence on telomere length. A few studies have demonstrated significant correlations between the telomere length of offspring and maternal and/or paternal telomere lengths. Positive correlations have also been observed for parental age at birth and offspring telomere length, particularly with paternal age. We decided to investigate the relationship between parental age and female offspring telomere length in one of the largest studies to date, by using existing leukocyte telomere length (LTL) data that were measured by a high-throughput quantitative PCR assay for multiple prospective nested case-control studies of various cancers and cardiovascular disease in the Nurses' Health Study (NHS). We derived probit scores for each nested case-control study to standardize for between-batch variability before pooling data. Participants included in this analysis were free of cancer and other major diseases at blood draw and were restricted to the 6,647 NHS participants who reported the years their mother and father were born on the 1976 baseline questionnaire. We calculated Spearman correlation coefficients and also used generalized linear regression to calculate least-square (LS) means of LTL probit score by maternal and paternal age at birth categories. LS means were adjusted for the participant's age at blood draw. Analyses of maternal age at birth categories were additionally adjusted for continuous paternal age at birth and vice versa. The mean age of participants at blood draw was 59 years. Mean maternal and paternal age at birth were 28 and 32 years, respectively. Maternal age and paternal age at birth were highly correlated (rS=0.77, P<0.0001). After controlling for participant's age at blood draw and maternal age at birth, paternal age at birth was positively associated with the participant's LTL at blood draw (P-trend=0.003). The adjusted LS mean LTL (probit score) across paternal age categories (15–24, 25–29, 30–34, 35–39, 40–44, and 45+ years) were −0.10, −0.01, 0.01, 0.02, 0.08, and 0.19, respectively. Among the NHS participants, a one year increase in paternal age at birth corresponded to an LT L difference observed for ∼6 months of younger age. Maternal age at birth was not associated with the participant's LTL at blood draw (P-trend=0.26). In our study population, we provide evidence of an association between older paternal age at birth and longer telomere length among female offspring, but not for maternal age at birth. These results are consistent with prior literature and support the existence of temporally-regulated paternal factors in the inheritance of leukocyte telomere length among their female offspring. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A85.

Abstract 2745: Genetic determinants of telomere length – a genome wide association study

Abstract Telomere plays a critical role in maintaining genome integrity. Telomere shortening is associated with the risk of many age-related diseases. Classical twin studies have shown that genetic components may contribute up to 80% of the heritability of telomere length. Previous association studies have reported several genetic loci in regulating telomere length, but the results have been inconsistent. In this study, we adopted a three-stage genome-wide association study (GWAS) design to identify the genetic determinants of telomere length. The mean telomere length was measured by quantitative real-time PCR. Genotyping were done by illumin's whole-genome SNP array in stage I and II, and by TaqMan assay in stage III. Multivariate linear regression analysis was applied to assess the association between genetic variants and telomere length adjusting for age and gender. In stage I, we analyzed 300K SNPs in 459 healthy controls and found 15,351 SNPs that were associated with telomere length at P<0.05. In phase II, we analyzed these 15,351 SNPs in two independent populations with GWAS data with 952 control subjects and 272 control subjects, respectively, and identified 18 SNPs, each with a combined P value < 10−4. Among them, two loci located at chromosome 20q11.22 and 14q21 were associated with telomere length with a significant P value < 10−7. We are in the process of genotyping these 18 SNPs and measuring telomere lengths in approximately 1,200 independent control subjects for stage III validation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2745. doi:10.1158/1538-7445.AM2011-2745

Abstract LB-424: A genome-wide association study identifies a locus on chromosome 14q21 as a predictor of leukocyte telomere length and as a marker of susceptibility to bladder cancer

Abstract Telomeres play a critical role in maintaining genome integrity. Telomere shortening is associated with the risk of many aging-related diseases. Classic twin studies have shown that genetic components may contribute up to 80% of the heritability of telomere length. In the study we report here, we used a multi-stage genome-wide association study (GWAS) to identify genetic determinants of telomere length. The mean telomere length in peripheral blood leukocytes was measured by quantitative real-time polymerase chain reaction. We first analyzed 300,000 single-nucleotide polymorphisms (SNPs) in 459 healthy controls, finding 15,120 SNPs associated with telomere length at P < 0.05. We then validated these SNPs in two independent populations comprising 890 and 270 healthy controls, respectively. Four SNPs, including rs398652 on 14q21, were associated with telomere length across all three populations (pooled P-values of < 10−5). The variant alleles of these SNPs were associated with longer telomere length. We then analyzed the association of these SNPs with the risk of bladder cancer in a large case-control study. The variant allele of rs398652 was associated with a significantly reduced risk of bladder cancer (odds ratio = 0.81; 95% confidence interval, 0.67–0.97; P = 0.025), consistent with the correlation of this variant allele with longer telomeres. We then conducted a mediation analysis to examine whether the association between rs398652 and reduced bladder cancer risk is mediated by telomere length, finding that telomere length was a significant mediator of the relationship between rs398652 and bladder cancer (P = 0.013) but that it explains only 14% of the effect. In conclusion, we found that the SNP rs398652 on 14q21 was associated with longer telomere length and a reduced risk of bladder cancer and that a small portion of the effect of this SNP on bladder cancer risk was mediated by telomere length. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-424. doi:10.1158/1538-7445.AM2011-LB-424

Correlation of Telomere Length in Blood, Buccal Cells, and Fibroblasts From Patients with Inherited Bone Marrow Failure Syndromes.

Abstract 1083Poster Board I-105 IntroductionPatients with dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS), have defects in telomere biology. Measurement of telomere length (TL) by flow fluorescence in situ hybridization (FISH) in white blood cell (WBC) subsets is a very important diagnostic tool in DC. Quantitative PCR (Q-PCR) is a high-throughput method of TL measurement that is currently used in large epidemiologic studies. It measures telomere length as a ratio of TTAGGG repeat copy number to a single copy gene number (T/S), and is often used on DNA derived from blood or buccal cells. There are limited data on tissue-specific correlations of TL and on the comparability of studies using different methods. In order to better understand tissue TL variability, we evaluated intra-individual correlations of DNA extracted from frozen blood, fibroblasts, and buccal cells by Q-PCR; and flow-FISH TL in WBC subsets. Patients and MethodsWe studied 21 patients: 5 Diamond-Blackfan Anemia (DBA), 6 DC, 5 Fanconi anemia (FA), and 4 Shwachman-Diamond Syndrome (SDS), enrolled in the National Cancer Institute's IBMFS study who contributed blood, buccal cells, and fibroblasts, and also had WBC flow-FISH TL measured. Genomic DNA was extracted from either whole blood (n=4) or the WBC pellet remaining after ficoll separation (n=17, primarily granulocytes) by manual Gentra Puregene. DNA was isolated from fibroblasts and buccal cells by phenol-chloroform extraction. TL was measured by Q-PCR of DNA from the three tissue types, and by flow-FISH in WBC subsets (lymphocytes and cell types matched to the types of WBC used in DNA extraction). We used the Wilcoxon signed-rank test to compare the median ranks of paired TL, and Spearman rank correlation coefficient to measure the strength of the associations between these measurements. ResultsTL in patients with DC was significantly (p<0.01) shorter than in patients with other IBMFS in all Q-PCR measurements of DNA from blood, fibroblasts, buccal cells; and flow-FISH WBC lymphocytes and matched cell types of WBC used in DNA extraction (86% were from granulocytes). Across all disorders, the median Q-PCR TL was longer in fibroblast and buccal cell DNA when compared with peripheral blood DNA (overall T/S ratio= 1.42 and 1.16 vs. 1.05, p=0.0002, 0.002, respectively). Although the absolute values varied, we observed in all IBMFS overall statistically significant (p≤0.001) intra-individual correlations in TL measured by Q-PCR in blood and fibroblast (r=0.67), blood and buccal cells (r=0.77), as well as fibroblast and buccal cells (r=0.67). When stratifying by disease subtype, statistically significant (p<0.05) correlations of Q-PCR in blood and buccal cells (r=0.9), and fibroblast and buccal cells (r=0.9) were observed in DC, and Q-PCR in blood and fibroblasts (r=1.0) in SDS. None of the Q-PCR tissue correlations reached statistical significance in FA or DBA. In addition, overall statistically significant (p≤0.01) correlations between TL in flow-FISH WBC subsets and Q-PCR in blood, fibroblast and buccal cells were observed. The correlations were driven mainly by the correlations with Q-PCR in blood and buccal cells in DC patients and with Q-PCR in fibroblasts in SDS patients. ConclusionsOverall Q-PCR TL was correlated between blood, buccal cells and fibroblasts and in comparison with flow-FISH TL, but there was some variability within different IBMFS. The poor correlation between tissues in FA and DBA might reflect blood-specific TL attrition in response to bone marrow stress. Most important, the correlation profile observed in DC suggests that the heritability of TL in DC is tissue independent. Blood or tissue Q-PCR TL appear to be useful in identifying individuals with DC who are unable to provide a fresh blood sample (e.g. epidemiologic studies or patients after bone marrow transplantation), although larger studies are needed to confirm or refute these findings. When possible, flow-FISH TL in subsets of leukocytes remains the modality of choice for the diagnosis of DC. DisclosuresLansdorp:Repeat Diagnostics Inc.: Equity Ownership.

The Heritability of Telomere Length Among the Elderly and Oldest-Old

AbstractA tight link exists between telomere length and both population doublings of a cell culture and age of a given organism. The more population doublings of the cell culture or the higher the age of the organism, the shorter the telomeres. The proposed model for telomere shortening, called the end replication problem, explains why the telomere erodes at each cellular turnover. Telomere length is regulated by a number of associated proteins through a number of different signaling pathways. The determinants of telomere length were studied using whole blood samples from 287 twin pairs aged 73 to 95 years. Structural equation models revealed that a model including additive genetic effects and non- shared environment was the best fitting model and that telomere length was moderately heritable, with an estimate that was sensitive to the telomere length standardization procedure. Sex-specific analyses showed lower heritability in males, although not statistically significant, which is in line with our earlier finding of a sex difference in telomere dynamics among the elderly and oldest-old.

The Heritability of Telomere Length Among the Elderly and Oldest-Old

A tight link exists between telomere length and both population doublings of a cell culture and age of a given organism. The more population doublings of the cell culture or the higher the age of the organism, the shorter the telomeres. The proposed model for telomere shortening, called the end replication problem, explains why the telomere erodes at each cellular turnover. Telomere length is regulated by a number of associated proteins through a number of different signaling pathways. The determinants of telomere length were studied using whole blood samples from 287 twin pairs aged 73 to 95 years. Structural equation models revealed that a model including additive genetic effects and non-shared environment was the best fitting model and that telomere length was moderately heritable, with an estimate that was sensitive to the telomere length standardization procedure. Sex-specific analyses showed lower heritability in males, although not statistically significant, which is in line with our earlier finding of a sex difference in telomere dynamics among the elderly and oldest-old.