%0 Journal Article %J Nature %D 2021 %T Regulatory genomic circuitry of human disease loci by integrative epigenomics. %A Boix, Carles A %A James, Benjamin T %A Park, Yongjin P %A Meuleman, Wouter %A Kellis, Manolis %K Chromatin %K Disease %K Enhancer Elements, Genetic %K Epigenesis, Genetic %K Epigenomics %K Female %K Gene Regulatory Networks %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Multifactorial Inheritance %K Organ Specificity %K Reproducibility of Results %X

Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete. Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits.

%B Nature %V 590 %P 300-307 %8 2021 02 %G eng %N 7845 %1 https://www.ncbi.nlm.nih.gov/pubmed/33536621?dopt=Abstract %R 10.1038/s41586-020-03145-z