A Functional Candidate Approach for Identification of Potential Maculopathic Disease Genes

Abstract

Purpose:: Pre-identifying genes as more likely candidates for elevated relevance to a retinal disease state facilitates investigations into the normative biology and function of the retina and macula. Genetic linkage studies to identify loci associated with specific macular phenotypes is one practicable and well-established method. Here we describe a candidate identification method using association of gene function in known maculopathic genes with fovea and foveomacularly expressed genes sharing those functions.

Methods:: Gene Ontology (GO) terms describing the function and subcellular localization of known retinopathic and maculopathic genes (as identified by RetNet) were collected from publicly available resources. These terms were used to seed a search against GO terms associated with a set of approximately 6800 genes identified as foveally or foveomacularly expressed. Genes that held terms in common with our panel of known disease genes were identified and further characterized in terms of their presumptive relevance as a functional candidate gene.

Results:: The 87 retinopathic genes chosen for this screen are represented by 276 unique GO terms, averaging 8 terms per gene. 41 of the 87 were re-identified using this approach. Among the 42 terms that individually represented greater than 0.5% of the total terms, 40 occurred and co-occured with genes in our fovea/foveomacular set, indicating shared function. Distribution of functions follows an exponential decay, with increasingly fewer numbers of genes possessing multiple retinopathic terms. 379 genes were identified possessing five or more retinopathic terms.

Conclusions:: We have identified a panel of GO terms representative of those functions defined by known retinopathic and maculopathic genes. These have been used to identify additional foveomacularly expressed genes that share common functional features with these disease genes and therefore have an increased likelihood for being macular or retinal disease candidate genes. We propose coupling this strategy with other candidate gene approaches to increase the power and rate of identification.

Keywords: gene screening • macula/fovea