title: 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.
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.|Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Christina
authors.initials: C
authors.lastname: Kiel
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.|Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Claire
authors.initials: C
authors.lastname: Lastrucci
authors.affiliation: Department of Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, and NIHR Biomedical Research Centre, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Luthert
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.|Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
mesh_terms: D053263:Gene Regulatory Networks; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism; D058499:Retinal Dystrophies / Q000235:genetics* / Q000378:metabolism