This study utilized two GWA datasets of Singaporean Chinese with 287 high myopia cases and 693 controls out of 2937 GWA samples, and a follow-up replication study in 3087 (959 high myopia cases and 2128 controls) Japanese. As we combined refractive error data from children and adults, high myopia is likely the more robust phenotype, as children with high myopia are very likely to remain highly myopic for life and phenotype reversal is extremely rare.
We found significant association of the CTNND2
gene on chromosome 5p15 to high myopia. The minor allele of rs6885224 was consistently associated with increased susceptibility to high myopia in SCORM (OR = 2.25, 95% CI:1.47–3.43) and SP2 (OR = 1.5, 95% CI:1.11–2.01), with evidence of replication in Japan dataset (OR = 1.14, 95%CI:1.02–1.27), thus suggesting that this gene is a potential candidate for high myopia across pediatric and adult age groups in two East Asian populations. A second CTNND2
SNP rs12716080 also had evidence of association to high myopia for the SCORM and SP2 cohorts (), with weaker evidence in the Japan cohort (). Both SNPs are in LD with r2
of 0.89 in Chinese and 0.937 in Japanese. In the HapMap and Human Genome Diversity projects, Chinese and Japanese have high similarity in population structure32;33
. Intuitively, CTNND2
may also be a genetic determinant for childhood high myopia, leading to high-grade myopia in adulthood. This finding may be useful for developing interventions in high risk children who carry the CTNND2
gene spans 933 Kb with 22 coding exons and resides within a 17.45 cM region on chromosome 5p15 previously found to be linked to high myopia in a family segregation study of three Hong Kong Chinese pedigrees (LOD = 4.68)34
. More recently, evidence of linkage replication for that region was determined in a small Asian subset of families with high-grade myopia (N = 10 families) (LOD=1.34)4
(). Of note, in non-human models, CTNND2
has been documented to play a crucial role in retinal morphogenesis, adhesion, and retinal cell architectural integrity via regulation of adhesion molecules35;36
. Interestingly, CTNND2
was one of five biologically plausible genes for high myopia examined by Lam et al.34
, who conducted direct sequencing of their coding regions to determine possible segregation with high myopia. In their study, five SNPs in the vicinity of CTNND2
were genotyped in a case-control association analysis using 94 cases with high myopia (SE at least −6.00 D) and 94 non-myopic controls. Evidence of segregation or association was not determined for CTNND2
in the Lam et al. study. It should be noted that both rs6885224 and rs12716080 were not assessed by Lam et al., and that the underpowered small sample size may have influenced the ability to detect evidence of association.
The strengths of our GWA studies are the reporting of association of unique genetic variants in two datasets of Singapore Chinese with very high rates of myopia, followed by the availability of the Japanese dataset for direct replication. The epidemic of myopia, especially in Chinese populations in Asia, may be due to either environmental factor (e.g., competitive educational systems with intensive near-work activity at an early age, limited outdoor activity)37;38
, genetic susceptibility, or both. We are, therefore, mindful that myopia is a complex disease with (up till now) no major, striking susceptibility locus. Rather, the disease susceptibility may be accounted for by multiple loci each exerting very small effect sizes. Therefore, it was not surprising that genome wide significance for single-marker analysis was not observed in our SCORM and SP2 datasets due to the small sample sizes, which have insufficient power to detect markers with small genetic effects (e.g., OR < 1.2). In order to reach the formal genome-wide threshold (P
), we estimate that we would need a sample size of > 9000, which we are currently working actively to achieve.
Despite missing this formal threshold, our observations with the CTNND2
SNPs are significantly consistent across all 3 cohorts (2 Chinese and 1 Japanese), and this argues against it being a false positive finding. Overall, our study suggests that although genetic factors could be influential (e.g., CTNND2
), they are in all likely to be very modest 1;2;23
In summary, we report novel association to high myopia of a common polymorphism of the gene CTNND2 in Chinese and Japanese cohorts. This new locus may inform functional variants for myopia, and provide insights into the eventual development of early intervention strategies to retard the progression of myopia in high risk populations.