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F. Pasutto, M. Krumbiegel, U. Schloetzer-Schrehardt, S. Uebe, M. Zenkel, C. Y. Mardin, N. Weisschuh, D. Paoli, F. E. Kruse, A. Reis; Genome Wide Association Study With Dna Pooling Identifies Variants at Cntnap2 Associated With Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2158.
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Genetic and non-genetic factors contribute to the development of pseudoexfoliation (PEX) syndrome, a complex, age-related, generalized matrix process which is frequently associated with glaucoma. In order to identify specific genetic variants underlying its aetiology, we performed a genome-wide association study (GWAS) using a DNA pooling approach.
Equimolar amounts of DNA samples of 80 subjects with PEX syndrome, 80 with PEX glaucoma (PEXG) and 80 controls, respectively, were combined into three separate pools and hybridized to 500K SNP arrays (Affymetrix). Array probe intensity data was analyzed and visualized with specially developed software tools GPFrontend and GPGraphics in combination with the GenePool program. For replication, independent German cohorts of 610 unrelated patients with PEX/PEXG and 364 controls as well as Italian cohorts of 249 patients and 190 controls were used.
Genotyping of selected SNPs in the CNTNAP2 locus revealed significant association between PEX syndrome/PEXG and two SNPs as well as their haplotype. The association found was confirmed in an independent German cohort but not in an Italian cohort. In the combined German cohorts the two SNPs remained significant after correction with permutation test (rs2107856: Pc=0.0044, rs2141388: Pc=0.0029).CNTNAP2 was found to be ubiquitously expressed in all human ocular tissues, particularly in the retina, and localized to cell membranes of epithelial, endothelial, smooth muscle, glial and neuronal cells.
Confirming efficiency of GWAS with DNA pooling approach, our data show compelling evidence for the association of CNTNAP2 with PEX syndrome and PEXG in German patients.
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