Novel Myopia Genes and Pathways identified from Syndromic forms of Myopia

摘要

Purpose: To test the hypothesis that genes known to cause clinical syndromes featuring myopia also harbor polymorphisms contributing to non-syndromic refractive error.Methods: Clinical phenotypes and syndromes that have refractive error as a recognized feature were identified using the Online Mendelian Inheritance in Man (OMIM) database. 154 unique causative genes were identified, of which 119 were specifically linked with myopia and 114 represented syndromic myopia (i.e. myopia and at least one other clinical feature). Myopia was the only refractive error listed for 98 genes and hyperopia the only refractive error noted for 28 genes, with the remaining 28 genes linked to phenotypes with multiple forms of refractive error. Pathway analysis was carried out to find biological processes over-represented within these sets of genes. Genetic variants located within 50 kb of the 119 myopia related genes were evaluated for involvement in refractive error by analysis of summary statistics from genome-wide association studies (GWAS) conducted by the CREAM consortium and 23andMe, using both single-marker and gene-based tests.Results: Pathway analysis identified several biological processes already implicated in refractive development through prior GWAS analyses and animal studies, including extracellular matrix remodelling, focal adhesion, and axon guidance, supporting the research hypothesis. Novel pathways also implicated in myopia development included mannosylation, glycosylation, lens development, gliogenesis and Schwann cell differentiation. Hyperopia was found to be linked to a different pattern of biological processes mostly related to organogenesis. Comparison with GWAS findings further confirmed that syndromic myopia genes were enriched for genetic variants that influence refractive errors in the general population. Gene-based analyses implicated 21 novel candidate myopia genes (ADAMTS18, ADAMTS2, ADAMTSL4, AGK, ALDH18A1, ASXL1, COL4A1, COL9A2, ERBB3, FBN1, GJA1, GNPTG, IFIH1, KIF11, LTBP2, OCA2, POLR3B, POMT1, PTPN11, TFAP2A, ZNF469). Conclusions: Common genetic variants within or nearby genes that cause syndromic myopia are enriched for variants that cause non-syndromic, common myopia. Analysis of syndromic forms of refractive error can provide new insights into the etiology of myopia and additional potential targets for therapeutic interventions.