Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma.
Hamel AR., Yan W., Rouhana JM., Monovarfeshani A., Jiang X., Mehta PA., Advani J., Luo Y., Liang Q., Rajasundaram S., Shrivastava A., Duchinski K., Mantena S., Wang J., van Zyl T., Pasquale LR., Swaroop A., Gharahkhani P., Khawaja AP., MacGregor S., International Glaucoma Genetics Consortium (IGGC) None., Chen R., Vitart V., Sanes JR., Wiggs JL., Segrè AV.
Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.