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Cristina Venturini, Jamie E Craig, Norbert Pfeiffer, Cornelia M van Duijn, Janey L Wiggs, Tin Aung, David A Mackey, Ananth C Viswanathan, Christopher J Hammond, Internatiol Glaucoma Genetics Consortium- IGGC; Common mechanisms underlying intraocular pressure identified in functional analysis of gene lists from genome-wide association study results in IGGC cohorts. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1662.
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Intraocular pressure is the main risk factor for glaucoma. Genome-wide association studies (GWAS), even when well powered, typically identify few genes, responsible for a fraction of heritability. Yet, under a plurigenic model for complex disease, many more loci are expected to lie undetected below the formal GWAS significance thresholds, due to their low effect sizes and perhaps across cohort genetic and environmental heterogeneity. A significant number among them are expected to share functional commonalities that may be possible to capture in existing functional annotation categories. The aim of the study is to explore the functional annotation categories over-represented in the genetic association profiles for intraocular pressure in the general populations.
This study is a meta-analysis of Gene Ontology enrichment analyses performed on GWAS results of twelve Caucasian independent cohorts (N=25847) and four Asians cohorts (N=7761) part of the International Genetics Glaucoma Consortium. Genes were assigned a significance level equal to the best associated SNP within 100kb of the transcript and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to identify sets of genes overrepresented in each of the cohorts. Fisher’s combined probability method was used for the meta-analysis.
Groups of genes enriched at very significant statistical levels were consistent across cohorts. These results suggest that genes involved in biological and cell adhesion (P= 1.91x10-20 and P= 1.43x10-19 respectively), located in the plasma membrane (P= 9.76x10-18) or, cellular junction (P= 2.68x10-15) and involved in calcium ion binding (P= 6.56x10-20) were significantly overrepresented in relation to intraocular pressure. These results were replicated in the Asian cohorts (biological and cell adhesion: P= 1.39x10-04 and P= 1.47x10-04; plasma membrane: P= 2.34x10-08; cell junction: P= 1.91x10-05; calcium ion binding P= 1.23x10-04).
These findings provide evidence that intraocular pressure in the general population is related to plasma membrane adhesion. This may have implications for prioritization work in future gene discovery analyses.
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