👤 Milly S Tedja

Refractive error (RE) and myopia are complex polygenic conditions with the majority of genome-wide associated genetic variants in non-exonic regions. Given this, and the onset during childhood, gene-regulation is expected to play an important role in its pathogenesis. This prompted us to explore beyond traditional gene finding approaches. We performed a genetic association study between variants in non-coding RNAs and enhancers, and RE and myopia. We obtained single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes, miRNA-binding sites, long non-coding RNAs genes (lncRNAs) and enhancers from publicly available databases: miRNASNPv2, PolymiRTS, VISTA Enhancer Browser, FANTOM5 and lncRNASNP2. We investigated whether SNPs overlapping these elements were associated with RE and myopia leveraged from a large GWAS meta-analysis (N = 160,420). With genetic risk scores (GRSs) per element, we investigated the joint effect of associated variants on RE, axial length (AL)/corneal radius (CR), and AL progression in an independent child cohort, the Generation R Study (N = 3638 children). We constructed a score for biological plausibility per SNP in highly confident miRNA-binding sites and enhancers in chromatin accessible regions. We found that SNPs in two miRNA genes, 14 enhancers and 81 lncRNA genes in chromatin accessible regions and 54 highly confident miRNA-binding sites, were in RE and myopia-associated loci. GRSs from SNPs in enhancers were significantly associated with RE, AL/CR and AL progression. GRSs from lncRNAs were significantly associated with all AL/CR and AL progression. GRSs from miRNAs were not associated with any ocular biometric measurement. GRSs from miRNA-binding sites showed suggestive but inconsistent significance. We prioritized candidate miRNA binding sites and candidate enhancers for future functional validation. Pathways of target and host genes of highly ranked variants included eye development (BMP4, MPPED2), neurogenesis (DDIT4, NTM), extracellular matrix (ANTXR2, BMP3), photoreceptor metabolism (DNAJB12), photoreceptor morphogenesis (CHDR1), neural signaling (VIPR2) and TGF-beta signaling (ANAPC16). This is the first large-scale study of non-coding RNAs and enhancers for RE and myopia. Enhancers and lncRNAs could be of large importance as they are associated with childhood myopia. We provide a confident blueprint for future functional validation by prioritizing candidate miRNA binding sites and candidate enhancers. Show less

To identify genes and genetic markers associated with corneal astigmatism. A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha ( In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the Show less