A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25

Abstract

Myopia and hyperopia are at opposite ends of the continuum of refraction, the measure of the eye's ability to focus light, which is an important cause of visual impairment (when aberrant) and is a highly heritable trait. We conducted a genome-wide association study for refractive error in 4,270 individuals from the TwinsUK cohort. We identified SNPs on 15q25 associated with refractive error (rs8027411, P = 7.91 × 10⁻⁸). We replicated this association in six adult cohorts of European ancestry with a combined 13,414 individuals (combined P = 2.07 × 10⁻⁹). This locus overlaps the transcription initiation site of RASGRF1, which is highly expressed in neurons and retina and has previously been implicated in retinal function and memory consolidation. Rasgrf1(-/-) mice show a heavier average crystalline lens (P = 0.001). The identification of a susceptibility locus for refractive error on 15q25 will be important in characterizing the molecular mechanism responsible for the most common cause of visual impairment.

Figure 1

Association scatter plot for SNPs in the RASGRF1 promoter region in the TwinsUK discovery cohort. Negative logarithms of the P values for the association of each SNP with spherical equivalence are plotted. The lead SNP is plotted in blue, with the meta-analysis P value for that SNP indicated. Genotyped SNPs are plotted as diamonds and imputed SNPs as circles, with the color indicating the degree of pairwise LD between the lead and neighboring SNPs. Red indicates strong pairwise LD, with r² ≥ 0.8; orange indicates moderate LD, with 0.5 < r² < 0.8 yellow indicates weak LD, with 0.2 < r² < 0.5; and white indicates no LD, with r² < 0.2. The associated SNPs lie in a 120-kb region of high LD, delineated by two local high-recombination spots at approximately 77,150 kb and 77,270 kb. The recombination rates are shown as light blue line and the locations of the genes with respect to these SNPs are shown as dark green arrows.

Figure 2

Association of rs8027411 with clinical myopia in the TwinsUK cohort. The values depicted by the diamonds represent ORs. Error bars, 95% CI.

Figure 3

Plot of the effect on refractive error observed for rs8027411 in the seven population panels participating in the study. For each population, the diamond square shows the β linear regression coefficient or the average difference in diopters for each additional copy of the T allele and the bars represent the standard error for the estimate. TwinsUK, the Twin Cohort recruited in London, UK; RS-I, the first Rotterdam Study cohort; RS-II, the second Rotterdam Study cohort; RS-III, the third Rotterdam Study cohort; ERF, the Erasmus Rucphen Family; 1958BC the 1958 British Birth Cohort; Aus, the Australian Twin Study.