The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

The effects of low-carbohydrate diets (≤45% of energy from carbohydrates) versus low-fat diets (≤30% of energy from fat) on metabolic risk factors were compared in a meta-analysis of randomized controlled trials. Twenty-three trials from multiple countries with a total of 2,788 participants met the predetermined eligibility criteria (from January 1, 1966 to June 20, 2011) and were included in the analyses. Data abstraction was conducted in duplicate by independent investigators. Both low-carbohydrate and low-fat diets lowered weight and improved metabolic risk factors. Compared with participants on low-fat diets, persons on low-carbohydrate diets experienced a slightly but statistically significantly lower reduction in total cholesterol (2.7 mg/dL; 95% confidence interval: 0.8, 4.6), and low density lipoprotein cholesterol (3.7 mg/dL; 95% confidence interval: 1.0, 6.4), but a greater increase in high density lipoprotein cholesterol (3.3 mg/dL; 95% confidence interval: 1.9, 4.7) and a greater decrease in triglycerides (-14.0 mg/dL; 95% confidence interval: -19.4, -8.7). Reductions in body weight, waist circumference and other metabolic risk factors were not significantly different between the 2 diets. These findings suggest that low-carbohydrate diets are at least as effective as low-fat diets at reducing weight and improving metabolic risk factors. Low-carbohydrate diets could be recommended to obese persons with abnormal metabolic risk factors for the purpose of weight loss. Studies demonstrating long-term effects of low-carbohydrate diets on cardiovascular events were warranted.

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.

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...