PQG Working Group

Carles Boix

PhD Candidate
MIT

Regulatory genomic circuitry of human disease loci by integrative epigenomicsAnnotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding, and gene-regulatory annotations highly incomplete. Here, we present EpiMap, a compendium of 10,000 epigenomic maps across 800 samples, which we use to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators, and downstream target genes. We use this resource to annotate 30,000 genetic loci 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 partition multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease-comorbidity patterns, and reveal both single-factor monotropic and multi-factor pleiotropic loci. Top-scoring loci frequently have multiple predicted driver variants, converging through multiple common-target enhancers, multiple common-tissue genes, or multiple genes/tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for complex trait dissection.