Determinants of telomere length across human tissues

Telomere length within an individual varies in a correlated manner across most tissues. Telomere length within individuals Telomeres are DNA-protein complexes that protect chromosome ends. Their length is of great interest because short telomeres are associated with specific diseases and with aging. Demanelis et al. measured telomere length from 952 Genotype-Tissue Expression (GTEx) project donors across tissues, of which 24 tissue types have measurements for more than 25 samples. This dataset shows that telomere length is not constant but is correlated across tissues. Most tissue telomeres shorten with age, but some, such as those in the testis and cerebellum, do not. In African Americans, telomeres are longer on average than those from individuals of primarily European descent across many tissue types. This observation is consistent with variability being passed from germ cells to zygote to differentiated cells during development. Science, this issue p. eaaz6876 INTRODUCTION Telomeres are DNA-protein complexes located at the end of chromosomes that protect chromosome ends from degradation and fusion. The DNA component of telomeres shortens with each cell division, eventually triggering cellular senescence. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and risk factor for age-related diseases. The extent to which TL in whole blood reflects TL in disease-relevant tissue types is unknown, and the variability in TL across human tissues has not been well characterized. The postmortem tissue samples collected by the Genotype-Tissue Expression (GTEx) project provide an opportunity to study TL in many human tissue types, and accompanying data on inherited genetic variation, gene expression, and donor characteristics enable us to examine demographic, genetic, and biologic determinants and correlates of TL within and across tissue types. RATIONALE To better understand variation in and determinants of TL, we measured relative TL (RTL, telomere repeat abundance in a DNA sample relative to a standard sample) in more than 25 tissue types from 952 GTEx donors (deceased, aged 20 to 70 years old). RTL was measured for 6391 unique tissue samples using a Luminex assay, generating the largest publicly available multitissue TL dataset. We integrated our RTL measurements with data on GTEx donor characteristics, inherited genetic variation, and tissue-specific expression and analyzed relationships between RTL and covariates using linear mixed models (across all tissues and within tissues). Through this analysis, we sought to accomplish four goals: (i) characterize sources of variation in TL, (ii) evaluate whole-blood TL as a proxy for TL in other tissue types, (iii) examine the relationship between age and TL across tissue types, and (iv) describe biological determinants and correlates of TL. RESULTS Variation in RTL was attributable to tissue type, donor, and age and, to a lesser extent, race or ethnicity, smoking, and inherited variants known to affect leukocyte TL. RTLs were generally positively correlated among tissues, and whole-blood RTL was a proxy for RTL in most tissues. RTL varied across tissue types and was shortest in whole blood and longest in testis. RTL was inversely associated with age in most tissues, and this association was strongest for tissues with shorter average RTL. African ancestry was associated with longer RTL across all tissues and within specific tissue types, suggesting that ancestry-based differences in TL exist in germ cells and are transmitted to the zygote. A polygenic score consisting of inherited variants known to affect leukocyte TL was associated with RTL across all tissues, and several of these TL-associated variants affected expression of nearby genes in multiple tissue types. Carriers of rare, loss-of-function variants in TL-maintenance genes had shorter RTL (based on analysis of multiple tissue types), suggesting that these variants may contribute to shorter TL in individuals from the general population. Components of telomerase, a TL maintenance enzyme, were more highly expressed in testis than in any other tissue. We found evidence that RTL may mediate the effect of age on gene expression in human tissues. CONCLUSION We have characterized the variability in TL across many human tissue types and the contributions of aging, ancestry, genetic variation, and other biologic processes to this variability. The correlation observed among TL measures from different tissues highlights the existence of host factors with effects on TL that are shared across tissue types (e.g., TL in the zygote). These results have important implications for the interpretation of epidemiologic studies of leukocyte TL and disease. TL in human tissues. Using a Luminex-based assay, TL was measured in DNA samples from >25 different human tissue types from 952 deceased donors in the GTEx project. TL within tissue types is determined by numerous factors, including zygotic TL, age, and exposures. TL differs across tissues and correlates among tissue types. TL in most tissues declines with age. 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 nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 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 affects TL in multiple tissue types and that TL may 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.