A genome-wide association analysis identified a novel susceptible locus for pathological myopia at 11q24.1

Abstract

Myopia is one of the most common ocular disorders worldwide. Pathological myopia, also called high myopia, comprises 1% to 5% of the general population and is one of the leading causes of legal blindness in developed countries. To identify genetic determinants associated with pathological myopia in Japanese, we conducted a genome-wide association study, analyzing 411,777 SNPs with 830 cases and 1,911 general population controls in a two-stage design (297 cases and 934 controls in the first stage and 533 cases and 977 controls in the second stage). We selected 22 SNPs that showed P-values smaller than 10(-4) in the first stage and tested them for association in the second stage. The meta-analysis combining the first and second stages identified an SNP, rs577948, at chromosome 11q24.1, which was associated with the disease (P = 2.22x10(-7) and OR of 1.37 with 95% confidence interval: 1.21-1.54). Two genes, BLID and LOC399959, were identified within a 200-kb DNA encompassing rs577948. RT-PCR analysis demonstrated that both genes were expressed in human retinal tissue. Our results strongly suggest that the region at 11q24.1 is a novel susceptibility locus for pathological myopia in Japanese.

Figure 1. Manhattan plot of the first stage results for pathological myopia.

Adjusted P-values obtained by the trend χ² test for 411,777 SNPs on autosomes in 297 pathological myopic cases and 934 general population controls are plotted in −log₁₀ scale according to their chromosome location.

Figure 2. Results of genome scan at 11q24.1 locus containing the BLID and LOC399959 genes.

(A) Adjusted P-values on −log₁₀ scale for SNPs examined for their association by the trend χ² test. (B) Structures, orientations and locations of the BLID and LOC399959 genes on NCBI Reference Sequence Build 36.1, together with pair-wise LD estimates of the SNP markers located within a 200-kb region encompassing the rs577948 marker (red box). Three additional SNP markers (rs11218544, rs11218553, and rs10892819), that showed adjusted P-value<10⁻² in the first stage, are also indicated.

Figure 3. Expression of the BLID and LOC399959 genes in the human retina.

RT–PCR analyses of BLID and LOC399959 expression in HeLa cells, the human Brain and the human retina. GAPDH was used as an internal control for cDNA quantification.