Novel Myopia Genes and Pathways Identified From Syndromic Forms of Myopia

Abstract

Purpose: To test the hypothesis that genes known to cause clinical syndromes featuring myopia also harbor polymorphisms contributing to nonsyndromic refractive errors.

Methods: Clinical phenotypes and syndromes that have refractive errors as a recognized feature were identified using the Online Mendelian Inheritance in Man (OMIM) database. One hundred fifty-four 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 and 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 overrepresented 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 error development through prior GWAS analyses and animal studies, including extracellular matrix remodeling, 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 nonsyndromic, common myopia. Analysis of syndromic forms of refractive errors can provide new insights into the etiology of myopia and additional potential targets for therapeutic interventions.

Figure 1

Chromosomal locations of all genes associated with syndromic ametropia in the OMIM database and the genes identified in the CREAM Consortium GWAS analysis.

Figure 2

Diagram of overrepresented biological processes in syndromic myopia and the associated genes.

Figure 3

Manhattan plot (A) and QQ plot (B) showing the observed degree of association (y-axis; minus log₁₀ of P value) in the CREAM Consortium GWAS for the 24,554 SNPs lying within 50 kb of the 107 autosomal OMIM derived myopia genes. The two horizontal lines in (A) indicate nominal (P = 0.05) and experiment-wise (P = 4.1E-05) level of statistical significance, respectively. The gray shaded region in (B) indicates the 95% confidence interval in which points would lie under the null hypothesis of no enrichment for SNPs associated with refractive error.

Figure 4

QQ plot for genes examined by VEGAS. The observed degree of association (y-axis; minus log₁₀ of P value) in the VEGAS analysis for 107 autosomal OMIM derived myopia genes. The gray shaded region in the QQ plot indicates the 95% confidence interval in which points would lie under the null hypothesis of no enrichment within genes for SNPs associated with refractive error.