Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal

Delgado, Dayana; Zhang, Chenan; Chen, Lin S.; Gao, Jianjun; Roy, Shantanu; Shinkle, Justin; Sabarinathan, Mekala; Argos, Maria; Lin, Tong; Ahmed, Alauddin; Islam, Tariqul; Rakibuz-Zaman, Muhammad; Sarwar, Golam; Shahriar, Hasan; Rahman, Mahfuzar; Yunus, Mohammad; Jasmine, Farzana; Kibriya, Muhammad G.; Ahsan, Habibul; Pierce, Brandon L.

doi:10.1136/jmedgenet-2017-104922

Cited by 39 publications

(41 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We lack detailed monitoring to exposure data (e.g., smoking and alcohol use) for GTEx donors; studies that can link human tissue samples to environmental and lifestyle histories are needed to better understand environmental determinants of TL across different tissues and cell types. Currently, all TL-associated SNPs have been identified in genome-wide association studies of leukocyte TL (12)(13)(14)(15); our study suggests some of these effects are also present in other tissue types, but larger studies of tissue-specific TL measurements are needed to characterize how these effects vary across tissues and cell types. Identifying variants that impact TL in all or most cell types (e.g., variants with effects on TL that may be present during development or in stem cells in multiple tissue types) may be ideal for evaluating the causal impact of TL on risk for a wide array of diseases (occurring in diverse tissues or cell types) using Mendelian randomization.…”

Section: Discussionmentioning

confidence: 83%

“…Prior genome-wide association studies (GWAS) have identified SNPs associated with leukocyte TL (12)(13)(14)(15). We constructed a weighted polygenic SNP score for each donor using nine leukocyte TL-associated SNPs, with higher score reflecting longer TL (see Methods and Table S6) (31).…”

Section: Leukocyte Tl-associated Genetic Variants and Tl In Other Tismentioning

confidence: 99%

“…However, long TL may increase risk for some types of cancer (9-11). Leukocyte TL is influenced by inherited genetic variation (single nucleotide polymorphisms [SNPs]), some of which reside near genes with roles in telomere maintenance (12)(13)(14)(15). Leukocyte TL is also associated with lifestyle factors (e.g., obesity) and exposures (e.g., cigarette smoking) (16,17).Epidemiologic studies of TL predominantly use blood (occasionally saliva) as a DNA source.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Determinants of telomere length across human tissues

Demanelis

Jasmine

Chen

et al. 2019

Preprint

Self Cite

131

162

View full text Add to dashboard Cite

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in non-blood, disease-relevant tissue types. Here we characterize variability in TL measurements for 6,391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) Project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation impacts TL in multiple tissue types, and that TL can mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health. ONE SENTENCE SUMMARYTelomere length varies by tissue type but is generally correlated among tissue types (positively) and with age (negatively). MAIN TEXTTelomeres are DNA-protein complexes located at the end of chromosomes that protect chromosome ends from degradation and fusion (1). The length of the DNA component of telomeres shortens as cells divide (2) with short telomeres eventually triggering cellular senescence (3,4). In most human tissues, TL gradually shortens over the life course, and TL shortening is considered a hallmark (and a potential underlying cause) of human aging (5). In human studies, short TL measured in leukocytes is associated with increased risk of aging-related diseases including cardiovascular disease (6) and type II diabetes (7) as well as all-cause mortality (8). However, long TL may increase risk for some types of cancer (9-11). Leukocyte TL is influenced by inherited genetic variation (single nucleotide polymorphisms [SNPs]), some of which reside near genes with roles in telomere maintenance (12)(13)(14)(15). Leukocyte TL is also associated with lifestyle factors (e.g., obesity) and exposures (e.g., cigarette smoking) (16,17).Epidemiologic studies of TL predominantly use blood (occasionally saliva) as a DNA source. Thus, our understanding of variation in TL, its determinants (e.g., demographic, lifestyle, and genetic factors), and its associations with disease phenotypes is based almost entirely on TL measured in leukocytes from whole blood. Few prior studies have compared TL in leukocytes to TL in other human tissue types; these prior studies are relatively small (<100 participants; <5 tissue types) but provide evidence that TL differs across tissue types and that TL measurements from different tissue types are correlated (18,19). However, larger studies of many additional tissue types are needed to gain a comprehensive understanding of variation in TL and its determinants within and across a wide range of human tissues and cell types. In order to address these gaps in our understanding of TL and its role as a biomarker of aging and disease risk, we measured TL in > 6,000 unique tissue samples, representing >20 distinct tissue types and > 950 individual don...

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Leukocyte Tl-associated Genetic Variants and Tl In Other Tismentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Determinants of telomere length across human tissues

Demanelis

Jasmine

Chen

et al. 2019

Preprint

Self Cite

131

162

View full text Add to dashboard Cite

show abstract

“…SNPs in RTEL1 are associated with glioma in large GWAS of this rare brain cancer. The glioma-associated RTEL1 SNPs are intronic, but functional studies have not yet been completed to understand their potential functions 148 – 152 . These findings are intriguing because patients with DC or HH due to autosomal recessive RTEL1 mutations often have abnormal brain development in the form of cerebellar hypoplasia 35 – 37 , 153 .…”

Section: The Advent Of Telomere Molecular Epidemiologymentioning

confidence: 99%

Beginning at the ends: telomeres and human disease

2018

View full text Add to dashboard Cite

Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential for chromosomal integrity) in human disease. Telomere biology disorders encompass a growing spectrum of conditions caused by rare pathogenic germline variants in genes encoding essential aspects of telomere function. Dyskeratosis congenita, a disorder at the severe end of this spectrum, typically presents in childhood with the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, accompanied by a very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other medical problems. In contrast, the less severe end of the telomere biology disorder spectrum consists of middle-age or older adults with just one feature typically seen in dyskeratosis congenita, such as pulmonary fibrosis or bone marrow failure. In the common disease realm, large-scale molecular epidemiology studies have discovered novel associations between illnesses, such as cancer, heart disease, and mental health, and both telomere length and common genetic variants in telomere biology genes. This review highlights recent findings of telomere biology in human disease from both the rare and common disease perspectives. Multi-disciplinary collaborations between clinicians, basic scientists, and epidemiologist are essential as we seek to incorporate new telomere biology discoveries to improve health outcomes.

show abstract

“…T/S ratio. Details of this methodology have been described previously 34 . Plate design 1was based on Ehrlenbach et al 35 and consisted of triplicates of 14 participant DNA samples per plate and six replicates of reference DNA sample, with telomere sequence and RPLP0 measured on the same plate.…”

Section: Measurement Of Ltl Using Qpcrmentioning

confidence: 99%

The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans

Delgado

Zhang

Demanelis

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h 2 ): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h 2 have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5,069 Bangladeshi adults with substantial relatedness. For each of the 7,254 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (T shared ). We then estimated the association between T shared and the squared pairwise difference in LTL ((ΔLTL) 2 ) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (ϕ).The association between T shared and (ΔLTL) 2 was inverse among all relative pair types. In a metaanalysis including all relative pairs (ϕ >0.05), the association between T shared and (ΔLTL) 2 (P=0.002) was stronger than the association between ϕ and (ΔLTL) 2 (P=0.45). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h 2 despite telomere "reprogramming" during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h 2 attributable to direction transmission.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

show abstract

Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal

Cited by 39 publications

References 50 publications

Determinants of telomere length across human tissues

Determinants of telomere length across human tissues

Beginning at the ends: telomeres and human disease

The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans

Contact Info

Product

Resources

About