Genetic pathways underlying the initiation and progression of age-related macular degeneration (AMD) have not been yet sufficiently revealed, and the correlations of AMD’s genotypes, phenotypes, and disease spectrum are still awaiting resolution. We are tackling both problems with systems biology phylogenetic parsimony analysis. Gene expression data (GSE29801: NCBI, Geo) of macular and extramacular specimens of the retinas and retinal pigment epithelium (RPE) choroid complexes representing dry AMD without geographic atrophy (GA), choroidal neovascularization (CNV), GA, as well as pre-AMD and subclinical pre-AMD were polarized against their respective normal specimens and then processed through the parsimony program MIX to produce phylogenetic cladograms. Gene lists from cladograms’ nodes were processed in Genomatix GePS to reveal the affected signaling pathway networks. Cladograms exposed a highly heterogeneous transcriptomic profiles within all the conventional phenotypes. Moreover, clades and nodal synapomorphies did not support the classical AMD phenotypes as valid transcriptomal genotypes. Gene lists defined by cladogram nodes showed that the AMD-related deregulations occurring in the neural retina were different from those in RPE-choroidal tissue. Our analysis suggests a more complex transcriptional profile of the phenotypes than expected. Evaluation of the disease in much earlier stages is needed to elucidate the initial events of AMD. 1. Introduction Age-related macular degeneration (AMD) is the main cause of permanent central blindness in the developed countries [1]. It manifests in drusen formation and degeneration/atrophy of the retinal pigmented epithelium (RPE) and neural retina, as well as the formation of abnormal choroidal capillaries [2, 3]. In addition to aging as the principal risk factor, there are others such as smoking, diet, and genetic predisposition [3, 4]. However, it is not yet sufficiently resolved the exact genetic pathways underlying the initiation and progression of AMD and the relationship between its genotypes and phenotypes [1]. Although a more recent clinical classification of AMD has been published recently [5], we are using that of Newman et al. [1] since the study specimens were categorized in the public data according to their phenotypes (see Table 1 for details), these encompass (1) dry AMD, (2) choroidal neovascularization (CNV) or Wet AMD, (3) geographic atrophy (GA) in macular region of RPE, (4) GA/CNV, (5) pre-AMD, and (6) subclinical pre-AMD. These phenotypes are typically the progressing manifestations of the
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