Simple and complex retinal dystrophies are associated with profoundly different disease networks

Abstract

Retinopathies are a group of monogenetic or complex retinal diseases associated with high unmet medical need. Monogenic disorders are caused by rare genetic variation and usually arise early in life. Other diseases, such as age-related macular degeneration (AMD), develop late in life and are considered to be of complex origin as they develop from a combination of genetic, ageing, environmental and lifestyle risk factors. Here, we contrast the underlying disease networks and pathological mechanisms of monogenic as opposed to complex retinopathies, using AMD as an example of the latter. We show that, surprisingly, genes associated with the different forms of retinopathies in general do not overlap despite their overlapping retinal phenotypes. Further, AMD risk genes participate in multiple networks with interaction partners that link to different ubiquitous pathways affecting general tissue integrity and homeostasis. Thus AMD most likely represents an endophenotype with differing underlying pathogenesis in different subjects. Localising these pathomechanisms and processes within and across different retinal anatomical compartments provides a novel representation of AMD that may be extended to complex disease in general. This approach may generate improved treatment options that target multiple processes with the aim of restoring tissue homeostasis and maintaining vision.

Figure 1. Principal differences between simple and complex retinal dystrophies (RD) and disease-gene network.

(a) Monogenetic non-syndromic and syndromic RDs are mainly driven by rare genetic variation. The disease onset can be very early, if the infant is born blind or develops severe vision loss soon after birth. Vision loss can also develop later in life. Complex retinopathies, such as age-related macular degeneration (AMD) have a later onset in life and are caused by a combination of common genetic risk factors, ageing and environmental/lifestyle factors. Figure was prepared using images from Servier Medical Art by Servier (http://www.servier.com/Powerpoint-image-bank), which is licensed under a Creative Commons Attribution 3.0 Unported License. (b) Disease/phenotype-gene network of 208 genes related to RD. Boxes represent genes and triangles diseases or phenotypes. Monogenic non-syndromic RD are coloured in yellow, monogenic syndromic RD are coloured in orange, and AMD in red. Green triangles represent diseases or phenotypes that manifest in tissues outside the eye (non-vision related). (c) Percentage of genes with a non-retinal phenotype for M-NS RD, M-S RD, and AMD.

Figure 2. Protein interaction networks and pathways associated to retinal dystrophies.

(a) Global protein interaction networks centred on RD gene products. Integrative literature based ‘omics’ protein-protein interaction networks for monogenic non-syndromic (M-NS), monogenic syndromic (M-S), and AMD-related disease gene products. The networks were retrieved from the HIPPIE database (http://cbdm.mdc-berlin.de/tools/hippie) and displayed using Cytoscape. (b) Association of proteins to different pathways based on the HPD database. Network representation of between the 208 RD proteins (round rectangles) and the number pathways a particular protein participates (black hexagons with white number inside indicating the number of pathways). The size of the hexagons correlates with the number of pathways a protein is associated to (see legend).

Figure 3. Functional classification of 208 RD genes and association to cell types or tissue compartments where this function contributes to vision-related tasks or to keeping the tissue integrity.

(a) Boxes represent the 208 RD genes, which are coloured according to their RD disease classification. Genes are boxed according to their functional classification and assigned to either the retinal cell type where this process plays a role, or to functions affecting other retinal compartments and retinal tissue development and integrity, or to presumably cell general functions. (b) Statistic of proteins in the different disease classes and their association to retina-specific and cell and tissue general functions.

Figure 4. Anatomy- and physiology-centric approach to understand complex and ageing-related retinopathies and (patho)physiological process networks.

(a) Schematic view summarizing the anatomy- and physiology-centric approach to molecular medicine where networks of processes are used to describe the anatomy and physiology, their interdependencies and modulation. (b) Selection of processes describing the tissue physiology in different retinal compartments and how they affect each other (see Supplementary Table S4 for a more complete list). On the left side the normal physiological process networks are shown and on the right side the pathological process networks together with their modulators (see symbols used in (a)).