Fuchs Endothelial Corneal Dystrophy (FECD) is a bilateral, generally symmetric, slowly progressing disorder of the corneal endothelium that was first described by Ernst Fuchs in 1910. This debilitating disorder becomes symptomatic in the fifth or sixth decade of life, and affects 2- 4 times more women than men. Clinical presentation of FECD varies, but often includes corneal edema that results in a loss of corneal clarity, painful episodes of recurrent corneal erosions, severely impaired visual acuity, and in some cases, blindness. Although medical management of symptoms may be attempted, most patients ultimately require corneal transplantation. As a result, FECD is a leading indication for corneal transplantation in the U.S. and in other developed countries. Excessive familial aggregation in first- and second-degree relatives has been reported, and several studies suggest that FECD is a common complex genetic disease. Investigators involved in the current proposal and others in the field have independently identified loci for FECD, but no study has examined large cohorts of patients with corneal dystrophies to assess genetic contributions. In the past two years we have successfully established a multi-center consortium to delineate the genetic architecture of FECD, and have assembled a large cohort of FECD subjects that are uniformly graded for disease severity. In addition, we have successfully conducted a genome-wide association study in >1425 cases and >2525 controls. To address deficiencies in our understanding the etiologic basis of FECD, we now propose to co-ordinate the activities of this consortium, and follow up our preliminary genome-wide association study results with detailed secondary analyses that include examination of other risk factors (e.g. smoking) and genotype-phenotype correlations at interesting loci (e.g. TCF4). The dearth of biological data on corneal proteins, the growing need for engineered tissue, and the significant resources garnered by our group offer a unique opportunity to advance this field.