Mapping Genetic Loci That Determine Leukocyte Telomere Length in a Large Sample of Unselected Female Sibling Pairs

Twin Research and Genetic Epidemiology Unit, St. Thomas' Hospital, London SE1 7EH, United Kingdom.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2006; 78(3):480-6. DOI: 10.1086/500052
Source: PubMed


Telomeres play a central role in cellular senescence and cancer pathobiology and are associated with age-related diseases such as atherosclerosis and dementia. Telomere length varies between individuals of the same age, is influenced by DNA-damaging factors such as oxidative stress, and is heritable. We performed a quantitative-trait linkage analysis using an approximate 10-cM genomewide map for mean leukocyte terminal-restriction fragment (TRF) lengths measured by Southern blotting, in 2,050 unselected women aged 18-80 years, comprising 1,025 complete dizygotic twin pairs. Heritability of mean batch-adjusted TRF was 36% (95% confidence interval [CI] 18%-48%), with a large common environmental effect of 49% (95% CI 40%-58%). Significant linkage was observed on chromosome 14 (LOD 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (LOD 2.4) and 3p26.1 (LOD 2.7). This is the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere variation in humans.

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    • "This may be consistent with overall effects of LTL marking effective biological age, and with heritability of more favorable, " healthier, " biological aging. Prior studies have demonstrated heritability of LTL, although estimates have varied widely from about 30% to 80% (Al-Attas et al., 2012; Andrew et al., 2006; De Meyer et al., 2007; Jeanclos et al., 2000; Nordfjall et al., 2005, 2010; Slagboom et al., 1994; Vasa-Nicotera et al., 2005; Wong et al., 2011). In addition, some studies have suggested a uniparental inheritance effect, with stronger inheritance from father to child (Njajou et al., 2007; Nordfjall et al., 2010) or mother to child (Broer et al., 2013). "
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    ABSTRACT: 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 h(2) = 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. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Neurobiology of aging
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    • "shown that Rtel is important in the disassembly of T-loops during replication (Vannier et al. 2012). Mapping approaches in humans have been much more extensive, and a number of loci were initially identified to contribute to leukocyte telomere length variation (Vasa-Nicotera et al. 2005; Andrew et al. 2006; Mangino et al. 2009). The causative gene in one locus from chromosome 12, identified by Vasa-Nicotera et al. (2005), was eventually shown to encode for Bicaudal-D homolog 1 (BICD1) (Mangino et al. 2008). "
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    ABSTRACT: Telomeres represent the repetitive sequences that cap chromosome ends and are essential for their protection. Telomere length is known to be highly heritable and is derived from a homeostatic balance between telomeric lengthening and shortening activities. Specific loci that form the genetic framework underlying telomere length homeostasis are, however, not well understood. To investigate the extent of natural variation of telomere length in Arabidopsis thaliana, we examined 229 worldwide accessions by terminal restriction fragment analysis. The results showed a wide range of telomere lengths that are specific to individual accessions. To identify loci that are responsible for this variation, we adopted a quantitative trait loci (QTL) mapping approach with multiple recombinant inbred line (RIL) populations. A doubled haploid RIL population was first produced using centromere mediated genome elimination between accessions with long (Pro-0) and intermediate (Col-0) telomere lengths. Composite interval mapping analysis of this population along with two established RIL populations (Ler-2/Cvi-0 and Est-1/Col-0) revealed a number of shared and unique QTLs. QTLs detected in the Ler-2/Cvi-0 population were examined using near isogenic lines which confirmed causative regions on chromosomes 1 and 2. In conclusion, this work describes the extent of natural variation of telomere length in Arabidopsis thaliana, identifies a network of QTLs that influence telomere length homeostasis, examines telomere length dynamics in plants with hybrid backgrounds, and shows the effects of two identified regions on telomere length regulation. Copyright © 2014, The Genetics Society of America.
    Full-text · Article · Dec 2014 · Genetics
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    • "In humans, leukocyte telomere length (LTL) progressively shortens with age because of the inability of DNA polymerase to fully replicate the 3′ end of the DNA strand in mitotic division, and is frequently reported to be relatively shorter in aging-related diseases: such as Alzheimer's disease [2] and vascular dementia [3]. LTL varies among individuals with the same age, and is found to be inheritable in quantitative-trait linkage analyses of sib pairs, with heritability estimates ranging from 36% to 86% [4]–[7]. "
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    ABSTRACT: Leukocyte telomere length (LTL) is a predictor of aging and a number of age-related diseases. We performed genome-wide association studies of mean LTL in 2632 individuals,with a two-stage replication in 3917 individuals from Chinese populations. To further validate our findings, we get the results of 696 samples from a cohort of European ancestry. We identified two loci associated with LTL that map in telomerase reverse transcriptase (TERT; rs2736100, P = 1.93×10(-5)) on chromosome 5p15.33 and near keratin 80 (KRT80; rs17653722, P = 6.96×10(-6)) on 12q13.13. In Chinese population each C allele of rs2736100 and T allele of rs17653722 was associated with a longer mean telomere length of 0.026 and 0.059 T/S, respectively, equivalent to about 3 and 7 years of average age-related telomere attrition. Our findings provide new insights into telomere regulatory mechanism and even pathogenesis of age-related diseases.
    Full-text · Article · Jan 2014 · PLoS ONE
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