Affected Pedigree Member Linkage Study of Adult Onset POAG

Glaucoma is the second leading cause of blindness in the U.S. and the leading cause among African-Americans. Glaucoma includes a diverse group of disorders that cause damage to the optic nerve and can result in loss of peripheral and ultimately central vision. In most cases, elevated pressure inside the eye is felt to be a major cause of sight loss. Several forms of glaucoma are known to be inherited or to have a component of risk that is inherited. Between 13 and 47 percent of reported cases are familial. The majority of glaucoma cases develop in adulthood, after age forty. Glaucoma may occur alone (termed primary glaucoma) or in association with other conditions such as diabetes or eye injury. Glaucoma is also subdivided into open or closed angle glaucoma, depending on the physical cause of pressure elevation within the eye. Adult primary open angle glaucoma accounts for 60-70% of all cases of glaucoma. Adult primary open angle glaucoma occurs in the general population at a frequency between 0.63% and 1.25%. Inheritance in a clearly defined manner for some infantile and juvenile forms of glaucoma is well documented. For adult onset cases in which older relatives of patients may no longer be living and children are not yet affected with the disease, it can be difficult to directly determine the genetic mechanism underlying glaucoma. Nevertheless, there is abundant evidence that one gene or perhaps several genes cause glaucoma in a significant proportion of cases. For example, although the risk of developing glaucoma is less than 2% among the general population over age 40, siblings of affected individuals have a risk as high as 16%. Several studies on the genetics of glaucoma have indicated that some cases are caused by a single gene, while others are caused by several genes acting together. Primary open angle glaucoma is diagnosed more commonly than any other form of glaucoma. Due to the relatively high incidence of the disorder in the general population, it is a significant health problem and of considerable research interest. One method of studying glaucoma is to use juvenile and infantile forms to provide genetic clues to the causes and biology of the adult forms. Our lab is currently studying an infant born with glaucoma caused by a chromosomal aberration where a portion of chromosomes 13 and 6 have changed places. We have also used a large family with juvenile onset open angle glaucoma to localize a gene that causes this specific form of glaucoma to a small region of chromosome 1. By identifying the gene involved in each one of these forms of glaucoma, we may receive important clues about the cause of adult forms. The relatively late onset of the adult form makes it more difficult to study using traditional genetic analysis of large families, such as we have done for juvenile glaucoma, because of the difficulty in obtaining large families with many living affected members. Pairs or small groups of affected relatives are common, however. In this project we propose to use 100 pairs of relatives affected with glaucoma to identify a gene or genes causing adult primary open angle glaucoma using a method called affected pedigree member analysis (APM). The theory behind APM is that different pairs of relatives will have different portions of their genome (identified by genetic markers) that are identical, either by chance or by inheritance from a recent ancestor. Given many pairs of relatives with the same disease, caused by the same gene(s), genetic markers surrounding that gene have an increased likelihood of being identical within all pairs. Markers that are identical within some pairs, but different within others are not likely to be close to a gene that causes glaucoma in the population under study. Because the APM method looks for association between the marker and a gene that causes or contributes to the disease., we can detect genetic contributions of a gene to the disease regardless of whether the gene acts in a dominant or recessive manner or is one of many genes involved in the disease. There are four specific aims for this project. 1) We will collect DNA samples and detailed diagnostic information from 100 pairs or small groups of people with adult onset primary open angle glaucoma. We will also collect DNA samples from unaffected relatives whenever possible to increase the statistical power of the analysis. 2) The affected individuals will be genotyped at 100 highly informative genetic markers. We will use an efficient and cost-effective high throughput method of genotyping. This number of markers will serve as a first pass through the genome. 3) The genotypes collected in aim 2 will be analyzed using the APM method. Significant associations between glaucoma and any of the genetic markers used will be further investigated by genotyping unaffected relatives (to increase the power of the test) and by genotyping additional markers in the same region of the chromosome as the initial associated marker. Because we are part of the Cooperative Human Linkage Center, (part of the human genome project) we have more than 1800 genetic markers available for our use. These markers will also allow us to perform a secondary screen with more closely spaced markers in the event the first 100 markers fail to yield positive results. 4) Once an association between a specific region of a chromosome and the disorder has been confirmed, we will identify any genes in the region with a high probability of causing glaucoma. Such genes might include structural proteins from certain parts of the eye or proteins that control the flow of liquids through membranes. These genes will be evaluated in the small pedigrees for linkage to glaucoma and will undergo limited screening for mutations.