This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fuchs endothelial corneal dystrophy (FECD: MIM136800) is a common eye disease, affecting approximately 1% of the general US population. Initially asymptomatic, individuals eventually present with decreased vision, foreign body sensation and pain upon waking. Slit lamp (microscopic) examination initially shows focal thickenings of Descemet's membrane known as corneal guttae, with subsequent stromal edema, epithelia edema and, in advanced stages, painful bullous keratopathy. FECD is the most common inherited disease in the USA leading to corneal transplantation. In addition individuals undergoing cataract surgery with FECD are at significant risk for corneal decompensation, requiring subsequent corneal transplantation. Molecular data on the genetic basis of corneal dystrophies is limited. With a significant population at risk, the identification of genes that may contribute to the dystrophy would provide very useful information for counseling, implementation of standard methods for therapeutic intervention, and ultimately gene modulation and/or therapy. In this study, we have used the network built by the active, multi-center NEI-funded Cornea Donor Study as the nexus to identify families with FECD, as well as unrelated FECD cases and controls, using the consortium model. We have completed the family recruitment phase of the project and are currently finishing up case-control recruitment. Family history, clinical and other demographic information is being collected using a standardized instrument. Histopathologic confirmation of severely affected index cases has been obtained. Blood samples are being collected for molecular genetic analyses. A Web-based database developed specifically for this project facilitates multi-site data collection. We found FECD to be strongly heritable in our family sample, whether defined as a binary trait or as a severity score. Central corneal thickness, adjusted for confounding factors including age, sex, ocular pressure and previous eye surgery, is also highly heritable. An initial association study on previously identified FECD candidate genes, run on a limited number of families, suggests that the major genetic determinants explaining the observed heritability are novel. We are preparing to conduct a genomewide linkage scan on the family sample, comprising 322 families containing at least 572 sibling pairs, including 333 affected sibling pairs. Model-free linkage analysis, using the SIBPAL program in S.A.G.E., will be conducted on genetic marker data derived from DNA samples in conjunction with the clinical data on FECD. In addition, we will perform a genomewide association analysis including approximately 500 unrelated cases (including probands of families) and 500 controls. We are nearing completion of the recruitment phase for unrelated cases and controls. We anticipate that this study?the first FECD study to include a large number of families with severe disease and unrelated individuals?will lead to novel insights into the etiology of FECD and the biology of the corneal endothelium.
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