Three susceptible loci associated with primary open-angle glaucoma identified by genome-wide association study in a Japanese population

Abstract

Primary open-angle glaucoma (POAG) is the major type of glaucoma. To discover genetic markers associated with POAG, we examined a total of 1,575 Japanese subjects in a genome-wide association study (stage 1) and a subsequent study (stage 2). Both studies were carried out at a single institution. In the stage 1 association study, we compared SNPs between 418 POAG patients and 300 control subjects. First, low-quality data were eliminated by a stringent filter, and 331,838 autosomal SNPs were selected for analysis. Poorly clustered SNPs were eliminated by a visual assessment, leaving 255 that showed a significant deviation (P < 0.001) in the allele frequency comparison. In the stage 2 analysis, we tested these 255 SNPs for association in DNA samples from a separate group of 409 POAG and 448 control subjects. High-quality genotype data were selected and used to calculate the combined P values of stages 1 and 2 by the Mantel-Haenszel test. These analyses yielded 6 SNPs with P < 0.0001. All 6 SNPs showed a significant association (P < 0.05) in stage 2, demonstrating a confirmed association with POAG. Although we could not link the SNPs to the annotated gene(s), it turned out that we have identified 3 genetic loci probably associated with POAG. These findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.diagnosis ͉ SNP ͉ GWAS ͉ meta-analysis ͉ glaucoma genetics

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

“…23 A couple of recent GWAS for POAG have identified sequence variants and genetic loci associated with POAG susceptibility in populations of European and East Asian ancestry. 28,29 The advantages of GWAS include the fact that a specific disease model is not needed, which can allow identification areas of previously unsuspected pathogenesis. It seems likely that pathogenesis of most cases of glaucoma, excluding those in which single gene defects have been identified, may be due to contributions from many different polymorphisms.…”

Reply to Rao et al.: Appropriate study design for genome-wide association study replication to identify variants modestly associated with complex traits

“…It is also quite important to properly assess the data from multiple sites in order to gain statistical power and identify latent variants associated with complex traits, especially when no major risk gene or locus was observed in the initial genome-wide association study (GWAS). Unlike the SNPs on the genes strongly associated with age-related macular degeneration (AMD) (3), we could not identify such SNPs in POAG that reached the genome-wide significant threshold (2). This is probably due to the fact that glaucoma seems to have more heterogeneous phenotypes than AMD and multiple gene-gene and geneenvironment interactions, each with a small effect, thereby possibly playing critical roles in the onset of the disease.…”

“…This is probably due to the fact that glaucoma seems to have more heterogeneous phenotypes than AMD and multiple gene-gene and geneenvironment interactions, each with a small effect, thereby possibly playing critical roles in the onset of the disease. Therefore, we concluded that the discovered SNPs were ''modestly'' associated and would provide a foundation on which to build (2).…”

Genome-wide association studies: applications and insights gained in Ophthalmology

“…This gene has now been shown to be significant in multiple independent GWAS in both normal tension glaucoma (NTG; see later) and POAG. Some have suggested its role is therefore on optic nerve susceptibility, 25 perhaps via effects on the TGF-beta pathway. 34 Certainly its role in glaucoma is now established, and further understanding of its role and effect on phenotype is now warranted.…”