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Magda A. Meester, Mohsen Ghanbari, Adriana I Iglesias, H Springelkamp, S.J Erkeland, A. Dehghan, Cornelia van Duijn, O Franco, Caroline Klaver; Identification of microRNAs associated with glaucoma using GWAS data.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5584.
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© ARVO (1962-2015); The Authors (2016-present)
Genetic polymorphisms in microRNA (miRNA) genes or their binding sites (BS) within target genes are expected to contribute to phenotypic variance and risk of disease. We aimed to identify miRNAs and target genes that are involved in glaucoma using existing GWAS data on glaucoma endophenotypes.
Single Nucleotide Polymorphisms (SNPs) in miRNA sequences and miRNA BS were retrieved from online databases (e.g. PolymiRTS and miRNASNP) and literature. MiRNA SNPs and BS SNPs present in the GWAS data were evaluated for their associations with glaucoma endophenotypes including intraocular pressure (IOP), cup area, disc area and vertical cup-disc ratio (VCDR), using data from the International Glaucoma Genetics Consortium (IGGC). Target genes for the associated miRNAs were ranked according to their association with the studied traits and tested in cell lines by transfection experiments for regulation by the miRNAs. Associated miRNA BS SNPs were prioritized based on various criteria (e.g. eQTL data, miRNA and target gene expression, putative interaction score).
Out of 2,420 miRNA SNPs, 412 (17%) were available in IGGC GWAS data. After applying Bonferroni correction, two SNPs were significantly associated with VCDR and cup area (p-values <1.2×10-4). One of the SNPs is located in the pre-miRNA sequence, and has been shown to decrease the expression level of the mature miRNA. The other is located in the seed region and does not influence the expression of the miRNA. However, we showed that this SNP disrupts the regulatory interaction between the miRNA and CARD10, a gene associated to disc area.Out of 401,000 miRNA BS SNPs, 72,052 (18%) were present in IGGC GWAS data. Forty-seven miRNA BS SNPs (in twenty-one genes) were significantly associated with glaucoma endophenotypes (p-value threshold of <6.9×10-6). After prioritization, ten identified SNPs were considered candidates for functional validation. Two of these are located in the glaucoma-associated gene CDKN2B, and both were already described to disrupt the miRNA binding sites. This underscores the validity of the methods and prioritization strategy used in this study.
We have successfully identified SNPs in two miRNAs, and in multiple miRNA BS that are associated with glaucoma endophenotypes. These miRNAs and target genes may represent targets for miRNA-related therapies for glaucoma.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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