Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Susette Lauwen (Donders series 523)

13 December 2021

Promotors: prof. dr. A.I. den Hollander
Prof. prof. dr. D.J. Lefeber

Age-related macular degeneration: From GWAS to functional effects

Age-related macular degeneration (AMD) is an eye disease affecting the elderly population. Patients gradually lose the central part of their vision. There are two forms of late stage AMD: wet AMD and dry AMD. Wet AMD patients receive an injection in the eye of anti-vascular endothelial growth factor (VEGF), which slows down their disease progression. For dry AMD patients, there is currently no treatment available. A number of genetic risk factors have been identified for AMD by GWAS, and this PhD project focused on the functional effects of these risk factors. For this purpose, we explored the effect of genetic variants on mRNA level, on plasma protein level and we investigated the function of one AMD-associated gene (B3GLCT) in a cellular model. We performed a transcriptome-wide association study (TWAS) for AMD in 27 tissues, with use of imputed gene expression data. This analysis revealed 106 genes to be associated with AMD based on their predicted gene expression. We measured plasma protein levels of MMP9, TIMP3 and HPX in AMD patients vs. controls, and we investigated possible associations between plasma protein levels and genetic variants. We found plasma MMP9 levels to be significantly higher in individuals carrying the AMD-risk allele at the MMP9 locus, and in wet AMD patients. Our research into the role of B3GLCT in AMD revealed that loss of B3GLCT results in altered glycosylation of one of its target proteins, TSP1, but it did not impair secretion from retinal pigment epithelial (RPE) cells. This knowledge contributes to our understanding of AMD and could hopefully in the future help to identify therapeutic targets for this disease.