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Brian Yaspan, Louis R. Pasquale, Stephanie Loomis, Jae Hee Kang, Margaret A. Pericak-Vance, Michael A. Hauser, Jonathan L. Haines, Janey L. Wiggs, NEIGHBOR consortium investigators; Hypothesis Independent Pathway Analysis Identifies Biologic Pathways Associated With Poag In Data From The Neighbor And Glaugen Genomewide Association Studies. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4492.
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Using genome-wide association SNP data, we assessed biologic pathways as annotated in the KEGG (Kyoto Encyclopedia of Genes and Genomes) database for association with risk of primary open-angle glaucoma (POAG). Pathway analysis includes the entirety of the SNPs in the GWAS to examine associations that fall under the genome-wide significance threshold. The PARIS algorithm used in this study creates random pathways to mimic the size and structure of the actual pathways, to determine if the statistical association is due to the biologic properties of the pathway or instead its size and structure.
We conducted a POAG case-control analysis of 1002 cases and 1183 controls from the GLAUGEN study and 2,517 POAG cases and 2,428 controls from the NEIGHBOR study using the Illumina 660W quad platform. We analyzed each study individually for single-SNP association using a logistic regression model to test for association. A subsequent meta-analysis of the two studies was performed. Using the meta-analysis association p-values, we utilized the PARIS algorithm (Pathway Analysis by Randomization Incorporating Structure) to assess biologic pathways for association with POAG risk within the 209 KEGG pathways for association with POAG risk.
After multiple testing correction, we found 14 pathways associated with risk of POAG (p<0.001 for all pathways). These pathways are loosely grouped into three categories; metabolism, cellular adhesion and signaling, and autoimmune disorders. Twelve of these pathways contain a substantial amount of overlap, however, two, butanoate metabolism (hsa00650) and basal transcription factors (hsa03022) contain genes which do not overlap with any other pathway in the database, and thus are entirely independent associations.
A hypothesis-independent approach identified 14 KEGG pathways associated with risk of POAG. These pathways represent a variety of cellular functions. These results highlight the complexity of the genetic basis of POAG etiology.
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