A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14

Abstract

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10⁻¹⁴). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16-1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42-2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

Figure 1

Genome-wide signal intensity (Manhattan) plot of the discovery cohort Rotterdam Study-I. The statistical significance values across the 22 autosomes of each SNP’s association with refractive error (measured as spherical equivalent) are plotted as −log₁₀ P values. SNPs with minor allele frequency ≥ 0.01 were included. The blue horizontal line indicates P = 10⁻⁵ and the red line indicates P = 5 × 10⁻⁸.

Figure 2

Forest plot of associations for myopia (spherical equivalent ≤ −3 diopters) versus hyperopia (spherical equivalent ≥ +3 diopters). Forest plot of the estimated per-genotype odds ratio for top SNP rs634990 for the five studies separately and for the meta-analysis of all studies. RS-I, Rotterdam Study I; RS-II, Rotterdam Study II; RS-III, Rotterdam Study III; ERF, Erasmus Rucphen Family Study; TwinsUK, the Twin Cohort recruited in London; OR, odds ratio.

Figure 3

Regional plot at chromosome 15q14. Log₁₀ P values from the discovery cohort RS-I as a function of genomic position (HapMap release 22 build 36). The P value for the top SNP is denoted by the large diamond and P values for other genotyped and imputed SNPs are shown as smaller diamonds. P values for SNPs of unknown type are presented as squares. Superimposed on the plot are gene locations (green) and recombination rates (blue).