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K. H. Baratz, N. Tosakulwong, E. Ryu, W. L. Brown, L. A. Hecker, K. E. Branham, K. E. Schmid-Kubista, J. R. Heckenlively, K. R. Bailey, A. O. Edwards; Fuchs Endothelial Corneal Dystrophy: Identification of Novel Genes and Pathways Using a Genetic Approach. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4295.
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To identify genomic regions and genes associated with Fuchs corneal dystrophy using a genome-wide association study (GWAS) on a discovery subject group and replication in an independent group of subjects.
Participants enrolled in a study of the genetics of complex ocular traits were identified who had clinical documentation of the presence and extent of corneal guttae. Control subjects were ≥ 60 years of age, had no guttae, and had no corneal abnormality that would have prevented the detection of guttae. Each case was matched to two controls using age and gender, and a matched case-control GWAS study design was employed. After quality control filters were applied, genotype distributions from the lllumina 370K Beadchip panel were evaluated using additive genotype models. The initial GWAS analysis was on 303 subjects (101 cases, 202 controls) and candidate loci were identified. An additional 87 subjects (29 cases, 58 controls) from a second center were combined with the initial 303 subjects and the GWAS analysis repeated. Genomic loci with p-values less than 0.001 in the initial subjects that increased in significance with addition of the additional 87 subjects were selected for replication using a larger, independent, third group of subjects (150 cases, 150 controls, matched 1:1).
Twelve loci met the criteria for replication, and two showed similar levels and direction of association with Fuchs dystrophy. The first replicated locus localized to the protein tyrosine phosphatase receptor type G (PTPRG) gene on chromosome 3. A polymorphism in PTPRG was moderately associated with Fuchs in both the GWAS (P=3.7E-05) and the replication (6.6E-03) with an odds-ratio of 9 [95%CI: 2-37] for the homozygous risk allele in the replication group. The second locus spanned two genes on chromosome 18 (TCF4/FLJ4573) and was highly associated with Fuchs in both the GWAS (2.2E-11) and the replication (8.1E-14) with an odds-ratio of 44 [95%CI: 7-269] for subjects homozygous for the risk allele.
These two loci discriminate between subjects with and without Fuchs dystrophy with 74% accuracy. The proteins produced at these loci are involved in cell-cycle regulation, growth, and differentiation, suggesting that the pathogenesis of Fuchs dystrophy may be related to endothelial cell maintenance or replacement.
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