Allele expression (AE) analysis robustly measures cis-regulatory effects. Here, we present and demonstrate the utility of a vast AE resource generated from the GTEx v8 release, containing 15,253 samples spanning 54 human tissues for a total of 431 million measurements of AE at the SNP level and 153 million measurements at the haplotype level. In addition, we develop an extension of our tool phASER that allows effect sizes of cis-regulatory variants to be estimated using haplotype-level AE data. This AE resource is the largest to date, and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA‐methylation modifying enzymes DNMT3A or TET2. We used DNA‐methylation array and whole‐genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p < 8.6 × 10−7) to 3.08 years (EEAA, p < 3.7 × 10−18). Mutations in most CHIP genes except DNA‐damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all‐cause mortality (hazard ratio 2.90, p < 4.1 × 10−8) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 × 10−6) compared to those who were CHIP−/AgeAccelHG−. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG− were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.

No abstract

Transcriptional changes in Friedreich’s ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues—such as dorsal root ganglia, sensory neurons and cerebellum—in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.

We found that human intestinal organoids maintain the age of the patient from whom they are derived, as measured by the epigenetic clock. Unexpectedly, we found that crypts and spheroids derived from small intestine showed striking epigenetic age reduction, relative to the colon. BACKGROUND & AIMS:The epithelia of the intestine and colon turn over rapidly and are maintained by adult stem cells at the base of crypts. Although the small intestine and colon have distinct, well-characterized physiological functions, it remains unclear if there are fundamental regional differences in stem cell behavior or region-dependent degenerative changes during aging. Mesenchyme-free organoids provide useful tools for investigating intestinal stem cell biology in vitro and have started to be used for investigating agerelated changes in stem cell function. However, it is unknown whether organoids maintain hallmarks of age in the absence of an aging niche. We tested whether stem cell-enriched organoids preserved the DNA methylationbased aging profiles associated with the tissues and crypts from which they were derived. METHODS:To address this, we used standard human methylation arrays and the human epigenetic clock as a biomarker of age to analyze in vitro-derived, 3-dimensional, stem cell-enriched intestinal organoids. RESULTS:We found that human stem cell-enriched organoids maintained segmental differences in methylation patterns and that age, as measured by the epigenetic clock, also was maintained in vitro. Surprisingly, we found that stem cell-enriched organoids derived from the small intestine showed striking epigenetic age reduction relative to organoids derived from colon. CONCLUSIONS:Our data validate the use of organoids as a model for studying human intestinal aging and introduce methods that can be used when modeling aging or age-onset diseases in vitro. (Cell Mol Gastroenterol Hepatol 2020;9:527-541; https://doi.