Genes, pathways, and animal models in primary open-angle glaucoma

Abstract

Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells (RGCs) and consequently visual field loss. It is a complex and heterogeneous disease in which both environmental and genetic factors play a role. With the advent of genome-wide association studies (GWASs), the number of loci associated with primary open-angle glaucoma (POAG) have increased greatly. There has also been major progress in understanding the genes determining the vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA), intraocular pressure (IOP), and central corneal thickness (CCT). In this review, we will update and summarize the genetic loci associated so far with POAG, VCDR, DA, CA, IOP, and CCT. We will describe the pathways revealed and supported by genetic association studies, integrating current knowledge from human and experimental data. Finally, we will discuss approaches for functional genomics and clinical translation.

Figure 1

Schematic representation of the stages involved in genome-wide association studies (GWASs). GWASs are based on either a case/control or a population-based design in which single-nucleotide polymorphisms (SNPs) across the whole genome are genotyped. Outcome of GWASs are associated SNPs that are tagging candidate genes or genomic regions (loci). Identified genes may lead to identification of pathways involved in the disease.

Figure 2

Endophenotype. (a) Definition and relation of endophenotype, phenotype, and gene. (b) Use of endophenotype in the context of primary open-angle glaucoma.

Figure 3

Genes implicated in POAG. The pie diagram illustrates the number of loci that show association with POAG including the familial forms. Three big groups are defined based on whether loci show association with normal-tension glaucoma, high-tension glaucoma, or POAG in general.

Figure 4

Genes implicated in glaucoma and endophenotypes. The Venn diagram illustrates the number of loci that show association with (a) optic disc parameters and (b) intraocular pressure and central corneal thickness. The number of loci associated with only one trait is mentioned in parentheses after the trait name, and genes names are listed below. Loci that show association with two or more traits are shown in the appropriate segment. Genes in bold have also been associated with POAG.

Figure 5

Pathways possibly implicated in POAG revealed by linkage and association studies. The six different biological processes possibly implicated in POAG reviewed are shown in the figure. Map was built using Ingenuity Pathway Analysis (IPA). Solid lines imply direct relationships between proteins (eg, physical protein–protein interaction or enzyme–substrate); dotted lines imply indirect functional relationships, such as coexpression, phosphorylation/dephosphorylation, activation/deactivation, transcription, or inhibition. Proteins in bold correspond to known glaucoma genes. Genes genome-wide associated with CCT (*), VCDR and CA (±), CA only (¥), and VCDR only (¤).