Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is a complex disease that results from multiple genetic and environmental factors. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate target mRNAs and are frequently implicated in human diseases. Here, we investigated the association of genetic variants in miRNAs and miRNA-binding sites within gene 3'-untranslated regions (3'UTRs) with AMD using data from the largest AMD genome-wide association study. First, we identified three variants in miRNAs significantly associated with AMD. These include rs2168518:G>A in the miR-4513 seed sequence, rs41292412:C>T in pre-miR-122/miR-3591, and rs4351242:C>T in the terminal-loop of pre-miR-3135b. We demonstrated that these variants reduce expression levels of the mature miRNAs in vitro and pointed the target genes that may mediate downstream effects of these miRNAs in AMD. Second, we identified 54 variants (in 31 genes) in miRNA-binding sites associated with AMD. Based on stringent prioritization criteria, we highlighted the variants that are more likely to have an impact on the miRNA-target interactions. Further, we selected rs4151672:C>T within the CFB 3'UTR and experimentally showed that while miR-210-5p downregulates expression of CFB, the variant decreases miR-210-5p-mediated repression of CFB. Together, our findings support the notion that miRNAs may play a role in AMD.

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Keywords Age-related macular degeneration, AMD, GWAS, MicroRNA, MiRNA genetic variants, MiRNA-binding site
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Journal Human Mutation
Ghanbari, M, Erkeland, S.J, Xu, L, Colijn, J.M, Franco, O.H, Dehghan, A, … Meester-Smoor, M.A. (2017). Genetic variants in microRNAs and their binding sites within gene 3'UTRs associate with susceptibility to age-related macular degeneration. Human Mutation, 38(7), 827–838. doi:10.1002/humu.23226