The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

10 Years of GWAS Discovery: Biology, Function, and Translation

An Expanded View of Complex Traits: From Polygenic to Omnigenic

A main challenge in genome-wide association studies (GWAS) is to pinpoint possible causal variants. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions, and the presence of linkage disequilibrium leads to effects being statistically spread out across multiple variants. Post-GWAS annotation facilitates the selection of most likely causal variant(s). Multiple resources are available for post-GWAS annotation, yet these can be time consuming and do not provide integrated visual aids for data interpretation. We, therefore, develop FUMA: an integrative web-based platform using information from multiple biological resources to facilitate functional annotation of GWAS results, gene prioritization and interactive visualization. FUMA accommodates positional, expression quantitative trait loci (eQTL) and chromatin interaction mappings, and provides gene-based, pathway and tissue enrichment results. FUMA results directly aid in generating hypotheses that are testable in functional experiments aimed at proving causal relations.

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Functional mapping and annotation of genetic associations with FUMA

The Human Transcription Factors.

BackgroundGenomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive MethodsWe examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR–Cas9 genome editing in samples from patients ResultsOur data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a pot

/pdf/fto-obesity-variant-circuitry-and-adipocyte-browning-in-29mzh6rgqx.pdf

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density

Provided herein is a method for controlling a rate of fatty acid oxidation in mesenchymal cells, comprising modulating the expression or activity of ADCY5. The rate of fatty acid oxidation may be decreased by reducing the expression or activity of ADCY5. The rate of fatty acid oxidation may be increased by increasing the expression or activity of ADCY5. In some embodiments, the mesenchymal cell may be a mesenchymal stem cell, an adipocyte, an osteoblast, a chondrocyte, or a myocyte. In some embodiments, controlling the rate of fatty acid oxidation in mesenchymal stem cells comprises inhibiting fatty acid oxidation. In some embodiments, inhibiting fatty acid oxidation prevents development of Type 2 Diabetes (T2D). In some embodiments, controlling the rate of fatty acid oxidation in mesenchymal stem cells may comprise increasing the rate of fatty acid oxidation. Increasing the rate of fatty acid oxidation may promote bone formation.

Isabel S. Sousa

Papers

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density

Methods for treating metabolic disorders by targeting adcy5