Pathway Discovery in Macular Degeneration Using Genome-Wide Proteome, Transcriptome, and Epigenetic Analyses

We are identifying the molecular biological pathways altered by the genetic variants across the ARMS2 genomic region, or locus, in human retina. This study uses sophisticated “omics” approaches to accomplish these goals.

The biological pathways affected by the ARMS2 locus increase the odds of developing age-related macular degeneration (AMD) about 7-fold in homozygotes for the risk haplotype compared to the common non-risk haplotype. However, the mechanisms through which the genetic variants at the locus are mediated are controversial. Traditional genetic and biochemical methods have yet to identify the biological pathway through which the impact on disease risk is mediated. Indeed, it is unknown if the genetic risk is mediated through the hypothetical gene LOC387715, HTRA1, or perhaps some mechanisms unrelated to either. In order to identify the biological pathways altered by the genetic variants across this locus, we propose to compare the proteome and transcriptome of retinal tissue from donors homozygous for either the common protective or the risk haplotypes at the ARMS2 locus. Further, this project will provide insight and help determine the value of such so-called “omics” approaches for studying the pathophysiology of complex traits affecting the eye.