The cell and molecular biology of complex forms of glaucoma: updates on genetic, environmental, and epigenetic risk factors.

Glaucoma is a clinically and genetically heterogeneous disease. First-degree relatives of primary open-angle glaucoma (POAG) patients have a disease prevalence that is between 4 and 10 times higher than that of the general population, 1–3 and there is a higher disease concordance in monozygotic twins than in dizygotic twins. 4,5 These studies indicate the significant heritability of POAG; however, a simple mode of inheritance is not likely and cannot be assumed in genetic studies designed to identify POAG susceptibility genes. POAG is also complex clinically. The relationship between intraocular pressure (IOP) elevation and retinal ganglion cell degeneration is not simple, 6 as many individuals have IOP elevation without optic nerve damage, 7 and in some individuals, optic nerve degeneration develops without elevated IOP. 8 Recent studies have shown that POAG-related clinical features, including optic nerve parameters, 9,10 central corneal thickness, 11–14 and IOP, 15 are influenced by different sets of genes. Genetic and environmental risk factors and epigenetics are thought to influence complex traits such as POAG, normal tension glaucoma (NTG) and exfoliation syndrome–related glaucoma (Fig. 1). GENETIC RISK FACTORS FOR POAG The identification and characterization of POAG susceptibility genes would elucidate the molecular pathogenesis and could suggest new methods of diagnosis and treatment. The demonstration that the function of a particular enzyme or structural protein is impaired in POAG patients may lead to the development of novel drug therapies. The identification of DNA sequence changes associated with the disease could form the basis of diagnostic tests that are useful in identifying individuals at risk. The availability of such tests would provide a mechanism for early detection and timely treatment. Those individuals at risk who are identified early in the course of the disease and who begin therapy before significant damage to the optic nerve have the best chance of maintaining useful sight. Although POAG has a significant heritability, family-based linkage studies have not revealed POAG genes with significant population effect. The lack of such findings suggests that novel POAG genes have modest effect sizes and that large data sets with well-defined phenotypes are necessary for discovery. The formation of multiple consortia and collaborations has been crucial in the success of the genome-wide association studies approach by increasing sample sizes, thereby increasing statistical power, enabling replication of findings from individual studies, and establishing common methods of analysis. Common complex diseases often require more than 10,000 cases and controls for successful identification of the predisposing genes. 16 Genome-wide association studies have recently shown promising results for POAG gene discovery. Using an Icelandic population of 1,263 cases and 34,877 population controls, two single-nucleotide polymorphisms (SNPs) in an intergenic region between the CAV1 and CAV2 genes were found to confer modest risk for POAG (odds ratio [OR] 1.3). This finding was replicated in Caucasians of European ancestry and in a Chinese