Advances in the genomics of common eye diseases

Abstract

Genome-wide association studies (GWAS) and other genomic technologies have accelerated the discovery of genes and genomic regions contributing to common human ocular disorders with complex inheritance. Age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and myopia account for the majority of visual impairment worldwide. Over 19 genes and/or genomic regions have been associated with AMD. Current investigations are assessing the clinical utility of risk score panels and therapies targeting disease-specific pathways. DR is the leading cause of blindness in the United States and globally is a major cause of vision loss. Genomic investigations have identified molecular pathways associated with DR in animal models which could suggest novel therapeutic targets. Three types of glaucoma, primary-open-angle glaucoma (POAG), angle-closure glaucoma and exfoliation syndrome (XFS) glaucoma, are common age-related conditions. Five genomic regions have been associated with POAG, three with angle-closure glaucoma and one with XFS. Myopia causes substantial ocular morbidity throughout the world. Recent large GWAS have identified >20 associated loci for this condition. In this report, we present a comprehensive overview of the genes and genomic regions contributing to disease susceptibility for these common blinding ocular disorders and discuss the next steps toward translation to effective gene-based screening tests and novel therapies targeting the molecular events contributing to disease.

Figure 1.

Schematic diagram of the eye. The basic structures of the eye are labeled in black font and the ocular tissues affected by the disorders discussed in this review are labeled in blue font. The function of the eye is to transduce a light signal to an electrical impulse. Light enters the eye through the cornea is focused by the lens and then stimulates the photoreceptors of the retina. The photoreceptors transduce the light signal into an electrical impulse that travels through the optic nerve to the brain. AMD affects the retina, and in particular the macular region of the retina responsible for high acuity vision. The retinal pigment epithelium (also a site of damage in AMD) is the outermost layer of the retina just beneath the photoreceptors. Diabetic retinopathy also affects the retina, frequently causing damage to the macular region and also other parts of the retina. Elevated IOP in glaucoma is caused by a reduction in the rate of removal of intraocular fluid by the trabecular meshwork. The visual compromise in glaucoma is caused by damage to the optic nerve and elevated IOP is a significant risk factor for optic nerve degeneration. Myopia, or near-sightedness, is created when the image focal point occurs in front of the retina (not shown on this figure). This can occur when the eye is too long for it's inherent focusing power.

Figure 2.

Genes and genomic regions associated with age-related macular degeneration (AMD). Genetic and environmental risk factors are presented. CFH (complement factor H) and ARMS2 (age-related maculopathy susceptibility 2) are major genetic risk factors for the disease.

Figure 3.

Genes and genomics regions associated with glaucoma and the related quantitative traits. Variants associated with ocular quantitative traits related to glaucoma and (ellipses) and POAG are presented (rectangle). POAG can be divided into high-tension (HTG) and normal-tension (NTG) subgroups. Of the two genes associated with elevated IOP, one (TMCO1) is also associated with HTG. One gene associated with thin CCT (FNDC3B) is also associated with HTG. Three genomic regions associated with optic nerve parameters (CDKN2BAS, ATOH7 and SIX1/SIX6) are associated with HTG, and one of these, CDKN2BAS, is associated with both HTG and NTG. The CAV1/CAV2 genomic region is associated with HTG but not with any quantitative trait. The 8q22 genomic region is associated with NTG only.