Chromatin dynamics identifies 78 genes at loci associated with elevated intraocular pressure and primary open-angle...

Primary open-angle glaucoma (POAG) is a chronic neurodegenerative disorder, and elevated intraocular pressure (IOP) represents the major, and only modifiable, risk factor for the disease. We modeled increased IOP by treating three primary human trabecular meshwork (TM) cell strains with dexamethasone, then generated a high-resolution map of promoter-centered chromatin contacts and regulatory modules to decipher how the genomic architecture and epigenetic state of disease-associated loci contribute to pathogenesis. We identify dynamic changes in chromatin compartments and looping, cis-regulatory elements and transcription factor hubs corresponding to altered transcriptional profile. By integrating GWAS-associated variants with dexamethasone-induced 3D chromatin landscape, we discovered 26 IOP- and 52 POAG- candidate causal genes, which belong to vesicle transport, TLR, MAPK and hippo-YAP signaling pathways. We also uncovered transcriptional regulatory role of 103 non-coding lead variants. Our studies provide a mechanistic framework of genetic complexity associated with ocular hypertension and POAG pathogenesis in addition to targets for therapies.