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Nature DOI:10.1038/s41586-020-03145-z

Regulatory genomic circuitry of human disease loci by integrative epigenomics.

Publication TypeJournal Article
Year of Publication2021
AuthorsBoix, CA, James, BT, Park, YP, Meuleman, W, Kellis, M
Date Published2021 02

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.


Alternate JournalNature
PubMed ID33536621
Grant ListHG008155 / NH / NIH HHS / United States
HG009446 / NH / NIH HHS / United States
HG009088 / NH / NIH HHS / United States
HG007234 / NH / NIH HHS / United States
HG007610 / NH / NIH HHS / United States
GM113708 / NH / NIH HHS / United States
MH109978 / NH / NIH HHS / United States
MH119509 / NH / NIH HHS / United States
AG058002 / NH / NIH HHS / United States
GM087237 / NH / NIH HHS / United States