Age-Related Macular Degeneration: Genetics and Biology Coming Together

Abstract

Genetic and genomic studies have enhanced our understanding of complex neurodegenerative diseases that exert a devastating impact on individuals and society. One such disease, age-related macular degeneration (AMD), is a major cause of progressive and debilitating visual impairment. Since the pioneering discovery in 2005 of complement factor H (CFH) as a major AMD susceptibility gene, extensive investigations have confirmed 19 additional genetic risk loci, and more are anticipated. In addition to common variants identified by now-conventional genome-wide association studies, targeted genomic sequencing and exome-chip analyses are uncovering rare variant alleles of high impact. Here, we provide a critical review of the ongoing genetic studies and of common and rare risk variants at a total of 20 susceptibility loci, which together explain 40–60% of the disease heritability but provide limited power for diagnostic testing of disease risk. Identification of these susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

“…Microglia, the main retinal immune cells (macrophages) especially play a key role both in degenerative and inflammatory retinal diseases (Fritsche et al, 2014; Karlstetter, Scholz, Rutar, Wong, & Provis, 2015). Additionally, other cell types present at the vitreoretinal interface, such as hyalocytes, may contribute to the ERM contraction (Kohno et al, 2009).…”

Mikroglia und Immuntherapien bei degenerativen Netzhauterkrankungen

“…Umfangreiche genomweite Assoziationsstudien und Metaanalysen belegen eine genetisch bedingte Dysregulation des Komplementsystems bei der AMD [19]. Darüber hinaus sind aktivierte Mikroglia eng mit Drusen von Patienten mit frü-her AMD assoziiert [37].…”

“…Seit Veröffentlichung der ersten genomweiten Assoziationsstudien der AMD hat das Komplementsystem beträcht-liche Aufmerksamkeit im Bereich der Netzhautforschung erlangt [19]. Eine lokale Fehlregulation der alternativen Komplementfaktorkaskade in der Netzhaut gilt seither als gesicherter pathophysiologisch relevanter Mechanismus [60].…”

Complex trait genetics: mapping, correlation and causation

“…Primary open angle glaucoma (POAG) and age related macular degeneration (AMD) both show strong familial aggregation [302,303]. AMD is a progressive disease characterized by retinal neovascularisation or atrophic degeneration in the macular and accounts for more than half of all blindness worldwide [303].…”

“…Primary open angle glaucoma (POAG) and age related macular degeneration (AMD) both show strong familial aggregation [302,303]. AMD is a progressive disease characterized by retinal neovascularisation or atrophic degeneration in the macular and accounts for more than half of all blindness worldwide [303]. POAG is the most common type of glaucoma in populations of European ancestry, [141] and is characterized by a progressive destruction of the optic nerve leading to permanent visual loss.…”