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Abstract #45897 Published in IGR 13-2
Genome-wide association study of pseudoexfoliation syndrome in German population
Krumbiegel M; Uebe S; Ekici AB; Mardin CY; Welge-Lussen U; Weisschuh N; Gramer E; Gieger C; Wichmann H-E; Franke AMedizinische Genetik 2011; 23: 148-149
Pseudoexfoliation (PEX) syndrome represents a complex, late-onset, generalized disease of the extracellular matrix characterized by the progressive, stable deposition of abnormal fibrillar aggregates in various intra-and extraocular tissues. It is the most common identifiable cause of open-angle glaucoma accounting for about 25% of all open-angle glaucoma worldwide. The etiology of PEX is poorly understood, but two single nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene have been recently identified as strong genetic risk factors for both PEX syndrome and PEX glaucoma (PEXG). In order to identify further genetic variants underlying its etiology, we performed a genome-wide association study (GWAS) on German patients with PEX and PEXG using the Affymetrix Genome-wide Human SNP Array 6.0. After quality filtering and imputation, 1,564,797 SNPs were tested for association to pseudoexfoliation in a sample of 771 cases and 899 population controls of German descent from the KORA study. Association analysis yielded no genome-wide significant loci except the known susceptibility locus LOXL1, which was confirmed with an odds ratio of 2.98 at the SNP rs2165241 (p=1.43E-36). Subsequently, we selected 32 SNPs in 15 chromosomal regions showing nominally significant differences in allele frequencies (p(greater-than or equal to)2.64E-05) and genotyped these 32 SNPs in further 544 German patients with PEX and PEXG, using the TaqMan OpenArray platform. Genotypes of 1,190 individuals from the PopGen study were used as additional control sample. After quality control, 28 SNPs in 13 loci remained associated with nominal sig-nificance. In the combined data set of all 1,315 cases and 2,089 control subjects, the most significant p-value was observed at SNP rs8064995 (p=7.69E-06, OR=1.33) on chromosome 17, about 20 kb upstream of PRKCA gene locus. None of the 13 loci showed genome-wide significant association, suggesting that like in many other complex traits, most genetic factors in 3PEX must have small effect sizes requiring very large studies to be detected in G WA studies. Our study confirms the strong association of the LOXL1 locus with PEX/PEXG and identifies further candidates which have to be corroborated in larger cohorts.
M. Krumbiegel. Institute of Human Genetics, Erlangen, Germany.
Classification:
9.4.4.1 Exfoliation syndrome (Part of: 9 Clinical forms of glaucomas > 9.4 Glaucomas associated with other ocular and systemic disorders > 9.4.4 Glaucomas associated with disorders of the lens)
3.4.1 Linkage studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
3.6 Cellular biology (Part of: 3 Laboratory methods)
