Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect
01 Oct 2013-European Journal of Human Genetics (Nature Publishing Group)-Vol. 21, Iss: 10, pp 1163-1168
TL;DR: A high and very consistent heritability estimate for TL is found, evidence for a maternal inheritance component and the influence of parental age at birth on TL is investigated, and a positive association with paternal age is found.
Abstract: Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19,713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64-0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother-offspring (r=0.42; P-value=3.60 × 10(-61)) than father-offspring correlation (r=0.33; P-value=7.01 × 10(-5)), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10(-5)). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10(-30)) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10(-23)) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10(-10)). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.
Citations
More filters
TL;DR: The intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases are summarized.
272 citations
Cites background or result from "Meta-analysis of telomere length in..."
...However, in a recent study by Broer, et al., in over 19,000 subjects, the mother-offspring TL correlation was observed to be considerably stronger than the father-offspring correlation (Broer et al., 2013)....
[...]
...19,000 subjects, the mother-offspring TL correlation was observed to be considerably stronger than the father-offspring correlation (Broer et al., 2013)....
[...]
TL;DR: An exhaustive literature review has demonstrated negative effects on sperm quality and testicular functions with increasing paternal age, and the need to educate infertile couples on the disturbing links between increased paternal age and rising disorders in their offspring.
Abstract: Over the last decade, there has been a significant increase in average paternal age when the first child is conceived, either due to increased life expectancy, widespread use of contraception, late marriages and other factors. While the effect of maternal ageing on fertilization and reproduction is well known and several studies have shown that women over 35 years have a higher risk of infertility, pregnancy complications, spontaneous abortion, congenital anomalies, and perinatal complications. The effect of paternal age on semen quality and reproductive function is controversial for several reasons. First, there is no universal definition for advanced paternal ageing. Secondly, the literature is full of studies with conflicting results, especially for the most common parameters tested. Advancing paternal age also has been associated with increased risk of genetic disease. Our exhaustive literature review has demonstrated negative effects on sperm quality and testicular functions with increasing paternal age. Epigenetics changes, DNA mutations along with chromosomal aneuploidies have been associated with increasing paternal age. In addition to increased risk of male infertility, paternal age has also been demonstrated to impact reproductive and fertility outcomes including a decrease in IVF/ICSI success rate and increasing rate of preterm birth. Increasing paternal age has shown to increase the incidence of different types of disorders like autism, schizophrenia, bipolar disorders, and childhood leukemia in the progeny. It is thereby essential to educate the infertile couples on the disturbing links between increased paternal age and rising disorders in their offspring, to better counsel them during their reproductive years.
265 citations
Cites background from "Meta-analysis of telomere length in..."
...A significant correlation was also seen between advanced male age and telomere length, though maternal age played a more significant role [7]....
[...]
...A negative association was reported between telomere length and the age [7]....
[...]
...[6], telomere length [7], de novo mutation rate [8], chromosomal structure [6,9] and epigenetic factors [10]....
[...]
TL;DR: It is proposed, in the context of human evolution, that epigenetic drift may represent a case of epigenetic thrift, or bet-hedging, and emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction.
Abstract: It is now well established that the genomic landscape of DNA methylation (DNAm) gets altered as a function of age, a process we here call ‘epigenetic drift’. The biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear. We here provide a brief review of epigenetic drift, focusing on the potential implications for ageing, stem cell biology and disease risk prediction. It has been demonstrated that epigenetic drift affects most of the genome, suggesting a global deregulation of DNAm patterns with age. A component of this drift is tissue-specific, allowing remarkably accurate age-predictive models to be constructed. Another component is tissue-independent, targeting stem cell differentiation pathways and affecting stem cells, which may explain the observed decline of stem cell function with age. Age-associated increases in DNAm target developmental genes, overlapping those associated with environmental disease risk factors and with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated age DNAm signatures. Epigenetic drift is also influenced by genetic factors. Thus, drift emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction. Finally, we propose, in the context of human evolution, that epigenetic drift may represent a case of epigenetic thrift, or bet-hedging. In summary, this review demonstrates the growing importance of the ‘ageing epigenome’, with potentially far-reaching implications for understanding the effect of age on stem cell function and differentiation, as well as for disease prevention.
262 citations
Cites background from "Meta-analysis of telomere length in..."
...Curiously, age-associated epigenetic drift and telomere shortening share many similar properties: both processes are influenced by genotype (18,92,93), both have been proposed to lead to stem cell dysfunction (55,94), both are aggravated in men compared with women (18,91,92), both are tissue-independent phenomena (13,95), and both have been linked to disease, disease risk and disease risk factors (13,18,74,96–100)....
[...]
TL;DR: A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets.
251 citations
TL;DR: Findings on stress-related maternal-placental-fetal endocrine and immune/inflammatory processes that may mediate the effects of various adverse conditions during pregnancy on the developing human embryo and fetus are presented.
237 citations
References
More filters
TL;DR: A primer pair is presented that eliminates the problem of presumed impossible to measure telomeres in vertebrate DNA by PCR amplification with oligonucleotide primers designed to hybridize to the TTAGGG and CCCTAA repeats, allowing simple and rapid measurement of telomere length in a closed tube, fluorescence-based assay.
Abstract: It has long been presumed impossible to measure telomeres in vertebrate DNA by PCR amplification with oligonucleotide primers designed to hybridize to the TTAGGG and CCCTAA repeats, because only primer dimer-derived products are expected. Here we present a primer pair that eliminates this problem, allowing simple and rapid measurement of telomeres in a closed tube, fluorescence-based assay. This assay will facilitate investigations of the biology of telomeres and the roles they play in the molecular pathophysiology of diseases and aging.
3,014 citations
TL;DR: Telomere length is a biomarker of somatic cell aging in humans and is consistent with a causal role for telomere loss in this process, and fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro.
Abstract: When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explained by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a striking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublings per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.
2,228 citations
TL;DR: The structure of telomeres, the protective DNA-protein complexes at eukaryotic chromosomal ends, and several molecular mechanisms involved in telomere functions are described.
2,000 citations
TL;DR: A study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent–offspring trios at high coverage shows that the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child.
Abstract: father’s age of 29.7, the average de novo mutation rate is 1.20 3 10 28 per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father’s age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father’s age on the risk of diseases such as schizophrenia and autism.
1,712 citations
TL;DR: The results lend support to the hypothesis that telomere shortening in human beings contributes to mortality in many age-related diseases.
1,642 citations