Chromatin topology dynamics of dexamethasone-treated trabecular meshwork identifies 78 causal genes for intraocular pressure and primary open angle glaucoma [CUT&Run]

The physiology of trabecular meshwork (TM) controls aqueous humor outflow resistance and thereby intraocular pressure (IOP), a major risk factor for primary open-angle glaucoma (POAG). To decipher how GWAS-identified non-coding variants contribute to IOP and POAG, we generated a high-resolution map of genome topology and regulatory modules from primary human TM cell lines. Integrated analyses with dexamethasone-treated TM cells, a model of augmented IOP, demonstrate extensive changes in chromatin compartments, accessibility, looping, and histone marks that are highly concordant with transcriptional changes. By combining GWAS-associated variants with dexamethasone-induced chromatin looping, we discovered 26 IOP- and 52 POAG- candidate causal genes, belonging to key TM pathways, including integrin, transcriptional regulation of VENTX, and TNF signaling. Our studies provide a mechanistic framework for elucidating genetic complexity of IOP and pathogenesis of POAG and suggest new targets for therapies.