Genetics of glaucoma

Abstract

Genetic and genomic studies, including genome-wide association studies (GWAS) have accelerated the discovery of genes contributing to glaucoma, the leading cause of irreversible blindness world-wide. Glaucoma can occur at all ages, with Mendelian inheritance typical for the rare early onset disease (before age 40) and complex inheritance evident in common adult-onset forms of disease. Recent studies have suggested possible therapeutic targets for some patients with early-onset glaucoma based on the molecular and cellular events caused by MYOC, OPTN and TBK1 mutations. Diagnostic genetic tests using early-onset glaucoma genes are also proving useful for pre-symptomatic disease detection and genetic counseling. Recent GWAS completed for three types of common adult-onset glaucoma have identified novel loci for POAG (primary-open-angle glaucoma) (ABCA1, AFAP1, GMDS, PMM2, TGFBR3, FNDC3B, ARHGEF12, GAS7, FOXC1, ATXN2, TXNRD2); PACG (primary angle-closure glaucoma (EPDR1, CHAT, GLIS3, FERMT2, DPM2-FAM102); and exfoliation syndrome (XFS) glaucoma (CACNA1A). In total sixteen genomic regions have been associated with POAG (including the normal tension glaucoma (NTG) subgroup), 8 with PACG and 2 with XFS. These studies are defining important biological pathways and processes that contribute to disease pathogenesis.

Figure 1

Schematic diagram of the ocular anterior segment in open-angle and closed-angle glaucoma. Under normal conditions (open angle) the aqueous humor formed by the ciliary body flows around the lens and iris (blue arrows) and exits the eye through the trabecular meshwork, through Schlemm’s canal and empties into aqueous veins and the episcleral venous system. In the closed angle, the iris and lens are positioned anteriorly causing an obstruction of aqueous flow through the trabecular meshwork.

Figure 2

Image of an eye with exfoliation syndrome (XFS). The exfoliation material is evident as white fibrillar material on the lens and pupil margin.