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<p>Fuchs endothelial corneal dystrophy (FECD) is a complex, late-onset disorder that
is a frequent indication for corneal transplantation and affects women more frequently
than men. Although linkage and association studies in patients of European and Asian
ancestry have started to explain the genetic basis of this disorder, the mechanism
by which FECD develops is still unclear. Three projects were undertaken to help elucidate
the genetic basis of FECD. The first project examined a large, multigenerational family
that exhibited strong familial clustering of FECD and identified evidence of linkage
to chromosome 18. This locus that has also been implicated through work on large and
small FECD families as well as unrelated patients. The second project examined African-Americans
with FECD and is the first work to examine this population of patients with respect
to the FECD phenotype. Novel variants in three FECD candidate genes, <italic>COL8A2</italic>,
<italic>SLC4A11</italic>, and <italic>ZEB1</italic> were identified at approximately
the same rate as observed in patients of other ancestries, reinforcing the notion
that these genes only contribute to a small fraction of FECD genetic susceptibility.
Finally, the influence of environmental factors on FECD susceptibility was examined
through the use of a risk factor questionnaire given to cases and controls at the
time of study enrollment. Several factors, including gender, age, and cataracts, were
found to significantly affect FECD risk. Gender and the number of cataract surgeries
were found to significantly interact with a genetic variant, rs613872 in the <italic>TCF4</italic>
locus on chromosome 18 that has been consistently and reproducibly associated with
FECD, to influence FECD susceptibility. Together, these findings indicate that the
genetic basis of FECD is complex, and recent advances in the field show promise in
accelerating the pace of discovery that will hopefully develop better FECD treatments
in the near future.</p>
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