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Magda A. Meester, Mohsen Ghanbari, Johanna Maria Colijn, Stefan Erkeland, Abbas Dehghan, Caroline C W Klaver; In silico identification of miRNAs associated with AMD. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2622.
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© ARVO (1962-2015); The Authors (2016-present)
Genetic polymorphisms in microRNA (miRNA) sequences or their binding sites (BS) affect expression of target genes, and are therefore expected to contribute to phenotypic variance and risk of disease. We aimed to identify miRNAs and their target genes that are associated with age-related macular degeneration (AMD) in an in silico study on existing GWAS data.
Known variants in miRNA sequences and miRNA BS were retrieved from online databases (PolymiRTS, miRNASNP, PolymiRTS, and Patrocles) and from literature. MiRNA SNPs and BS SNPs present in GWAS studies were evaluated for their association with AMD using summary statistics (Fritsche, Nat Genet. 2013). Target genes for the associated miRNAs were ranked according to their association with AMD. MiRNA’s which bind to the site in which the SNP in the AMD gene was located were functionally evaluated by studying the expression of the miRNA in retina and brain tissue. Cis-eQTL data bases were screened to provide evidence for differential expression of genes related to the AMD-associated BS SNP.
Of all 2347 miRNA gene variants, 64 were present among the imputed variants in AMD GWAS studies. After applying Bonferroni correction, two of these variants were significantly associated with AMD (p-values 1.8x10-4 and 4.1x10-4). One of these was located in the seed region of an miRNA, and this variant significantly reduced the expression of the miRNA. The two miRNAs identified had hundreds of target genes; three of these were associated with AMD (p-values 1.3 x 10-4, 2 x 10 -12 and 3 x 10-8).Of the 410,000 miRNA BS variants, 22,000 SNPs were present in AMD GWAS studies. 22 miRNA BS variants in 13 genes were significantly associated with AMD (p-value threshold of <2.3×10-6). 6 of these SNPs represented the top SNP of an associated region. Most variants either disrupted existing miRNA BS or created new binding sites. 16 out of 38 of the potentially binding miRNAs were expressed in retina or brain. Cis-eQTL data for 9 SNPs showed up- or downregulation of 21 genes.
We have successfully identified variants in 2 miRNA sequences, and in 20 miRNA BS in genes that are associated with AMD. Expression of associated miRNA’s or target genes support these findings. These miRNAs or miRNA BS might represent targets for miRNA-related therapies for AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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