Systems-level analysis of age-related macular degeneration reveals global and subtype-specific functional pathways

Age-related macular degeneration (AMD) is a leading cause of human blindness in developed countries. While significant inroads have been made over the past decade, an integrated description of the molecular mechanisms underlying AMD has yet to emerge. Here we describe a systems-level transcriptome analysis of the retina and retinal pigmented epithelium (RPE)-choroid complex from 31 normal, 26 AMD, and 11 potential pre-AMD human eyes derived from the University of Iowa. Our analysis identifies cell-mediated immune responses as the central feature of dry AMD, wet AMD, and geographic atrophy (GA), and we confirm this finding using a second cohort of donor eyes obtained from the Lion's Eye Bank of Oregon. In addition, in the RPE-choroid, we identify the major up-regulated pathways in GA and wet AMD as apoptosis and angiogenesis, respectively. In the retina, a graded up-regulation of wound response, complement, and neurogenesis pathway genes strongly correlates with advanced stages of AMD, in parallel with a progressive down-regulation of key phototransduction processes. Finally, using expression signatures enriched in functional pathways, we assemble two detailed AMD interactomes that highlight modular gene expression programs that delineate and interconnect dry, wet, and GA AMD subtypes across both RPE-choroid and retina tissues. In total, these interactomes are comprised of over 150 genes of which 23 have been previously associated with AMD. These data provide new insights into the expression landscape of AMD pathophysiology, and reveal numerous new targets for AMD pharmaceuticals and diagnostics.