systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks

background: age-related macular degeneration (amd) is a leading cause of blindness that affects the central region of the retinal pigmented epithelium (rpe), choroid, and neural retina. initially characterized by an accumulation of sub-rpe deposits, amd leads to progressive retinal degeneration, and in advanced cases, irreversible vision loss. although genetic analysis, animal models, and cell culture systems have yielded important insights into amd, the molecular pathways underlying amd’s onset and progression remain poorly delineated. we sought to better understand the molecular underpinnings of this devastating disease by performing the first comparative transcriptome analysis of amd and normal human donor eyes. methods: rpe-choroid and retina tissue samples were obtained from a common cohort of 31 normal, 26 amd,and 11 potential pre-amd human donor eyes. transcriptome profiles were generated for macular and extramacular regions, and statistical and bioinformatic methods were employed to identify disease-associated gene signatures and functionally enriched protein association networks. selected genes of high significance were validated using an independent donor cohort. results: we identified over 50 annotated genes enriched in cell-mediated immune responses that are globally over-expressed in rpe-choroid amd phenotypes. using a machine learning model and a second donor cohort, we show that the top 20 global genes are predictive of amd clinical diagnosis. we also discovered functionally enriched gene sets in the rpe-choroid that delineate the advanced amd phenotypes, neovascular amd and geographic atrophy. moreover, we identified a graded increase of transcript levels in the retina related to wound response, complement cascade, and neurogenesis that strongly correlates with decreased levels of phototransduction transcripts and increased amd severity. based on our findings, we assembled protein-protein interactomes that highlight functional networks likely to be involved in amd pathogenesis. conclusions: we discovered new global biomarkers and gene expression signatures of amd. these results are consistent with a model whereby cell-based inflammatory responses represent a central feature of amd etiology,and depending on genetics, environment, or stochastic factors, may give rise to the advanced amd phenotypescharacterized by angiogenesis and/or cell death. genes regulating these immunological activities, along with numerous other genes identified here, represent promising new targets for amd-directed therapeutics and diagnostics.