Age Related Macular Degeneration (AMD) is a leading cause of legal blindness in Australia, with 1 in 7 Australians over 50 with early signs of the disease. and affects the retinal pigment epithelium (RPE). Currently there are currently no treatments that prevent progression to the vision-threatening late stages of the disease. Reticular Pseudodrusen (RPD) is a subtype associated with higher risk of AMD progression. Numerous genetic variants associated with AMD have been discovered with Genome Wide Association Studies (GWAS), but the mechanisms of many genetic risk factors remain unknown. Improved understanding of the genetic architecture of AMD might reveal mechanisms and therapeutic targets.
MicroRNAs (miRNAs) downregulate sets of genes based on interaction of a seed sequence within the miRNA and target mRNAs. Several miRNAs have been linked to retinal gene regulation. To investigate their role in AMD, we examined miRNA gene expression in in vitro RPE cells differentiated from induced pluripotent stem cells (iPSCs) derived from people with AMD.
Sixty-one AMD samples were obtained (AMD+/RPD+ = 29, AMD+/RPD- = 32) and profiled for miRNA and mRNA expression and genotype. We identified three miRNA expression quantitative trait loci (eQTLs) with the software QTLtools. Target mRNAs for these miRNAs were identified using mirTarget. Expression of many of the target genes of two of these miRNAs was negatively correlated with miRNA expression in the RPE cells, suggesting a gene regulatory role for those miRNAs in RPE. Colocalisation analysis of these signals with retinal GWAS results were performed to gain further insights into potential roles of these miRNAs in AMD.
Although no significant eQTL differences were observed between groups with and without the high-risk RPD subtype, several miRNAs were differentially expressed, suggesting subtype- specific regulation.