ARRA IMPACT REPORT:
Public Health Burden
Glaucoma is a family of irreversible blinding diseases characterized by progressive optic neuropathy (optic nerve degeneration diagnosed by visual field defects). Glaucoma affects more than 2 million adults 40 years and older in the United States. It is the leading cause of blindness among Hispanic and African Americans and is the third most prevalent cause of visual impairment and blindness among Caucasian Americans. Although genes contributing to early-onset, rare (Mendelian) forms of glaucoma have been known, molecular insights for late-onset, common forms have eluded biologists. Hence, the National Eye Institute launched an ARRA initiative to conduct large-scale genome-wide association studies (GWAS) with the statistical power to identify genetic variants relevant to these genetically complex diseases.
Genome Wide Association Studies—the NEIGHBOR Consortium
Incidence of Primary Open Angle Glaucoma (POAG), the most common form of glaucoma, is consistent with a significant genetic predisposition (first-degree relatives have risk about 10 times that of the general population). Despite the high heritability of POAG, susceptibility cannot be linked to a single underlying gene or simple mode of inheritance.
ARRA funds helped leverage existing DNA sample collections and the GLAUcoma Genes and ENvironment (GLAUGEN) study with newly collected DNA samples from POAG patients and controls to assemble the largest genetic study of glaucoma to date, the NEI Glaucoma Human genetics collaboration (NEIGHBOR).1 The consortium of 22 investigators at 12 institutions throughout the United States collected genetic samples and clinical phenotypes from 6,633 individuals (3,146 cases of POAG, 3,487 controls) using a harmonized definition of POAG. Genetic data from NEIGHBOR are available as a resource to the scientific community on the Database of Genotype and Phenotype,2 as are data3 from another ARRA-supported International Collaborative Twin Study of Refractive and Glaucoma Endophenotypes.4
NEI is now creating the NEIGHBORHOOD (NEIGHBOR Heritable Overall Operational Database) consortium and database, whose goals are to expand the collection of glaucoma cases, to collect exacting clinical data for detailed classifications of POAG phenotypes, and to correlate them with genetic variations of the disease. NEIGHBORHOOD will include cases and controls from the Nurses’ Health Study and Health Professionals Follow-up Study, the Women’s Genome Health Study, Mayo Clinic, Marshfield Clinic, and the University of Iowa Ophthalmology clinics. NEIGHBORHOOD will create a rich resource for future studies of other POAG related traits as well as gene-gene and gene-environment interactions.
Central Corneal Thickness
Central corneal thickness (CCT) is an important risk factor for POAG; differences in CCT between individuals of different racial backgrounds may relate to the disparity in glaucoma incidence. Using the GWAS dataset, NEIGHBOR investigators tried to verify associations between previously published CCT regions and glaucoma. Although they were unable to replicate any of the previous CCT association results, the CCT linked regions did point to new genes, neurotrimin and CNTNAP4, that may increase POAG susceptibility in a subset of cases.5
New Genetic Loci for Glaucoma and Optic Nerve Degeneration
The NEIGHBOR GWAS identified two genetic regions significantly associated with glaucoma. On chromosome region 9p21, strong genetic evidence pointed to the CDKN2BAS gene. The product of this gene blocks a protein involved in regulating the cell cycle, which may play a role in cell death of optic nerve cells. SIX1/SIX6 on chromosome 14q23 was the second genetic hit. SIX1/SIX6 plays a role in controlling optic nerve area and the size ratio of the optic nerve’s “cup” to its “disc”, a phenotype used to help diagnose glaucoma that clinicians can measure by taking a picture of the back of the eye.
Although POAG is often initiated when abnormally high fluid pressure in the eye causes cells in the optic nerve to die, some patients have normal pressure glaucoma (NPG). By re-analyzing the data just focusing on NPG patients and controls, the geneticists found associations with CDKN2BAS, as well as a new region, 8q22, containing the LRP12 and ZFPM2 genes. Follow up cell biology studies showed that a common downstream target of these NPG genes is the Transforming Growth Factor-beta, a key signaling molecule that regulates cell growth and survival throughout the body and has been previously associated with glaucoma. These regions were also significant when the team focused on patients with pseudoexfoliation glaucoma. Because optic nerve degeneration is the common endpoint for different forms of glaucoma, uncovering the underlying genes and mechanisms is a critical step in developing therapies.6
Contributing NIH Institutes & Centers
- National Eye Institute (NEI)