We have performed a genome-wide survey for corneal astigmatism across 8,513 individuals, where the discovery phase combines the data from two GWAS performed in Chinese and Malay adults, and the replication phase included Asian Indian adults, Chinese children and family trios. We observed a strong and consistent association with the onset of corneal astigmatism at the PDGFRA gene locus on chromosome 4q12 across all five Asian cohorts, with three SNPs in this locus exhibiting evidence stronger than genome-wide significance in the meta-analysis. To the best of our knowledge, this is the first GWAS to investigate the genetic etiology of corneal astigmatism in a genome-wide fashion.
gene spans 69 kb with 23 coding exons and resides on chromosome 4q12. The receptor for platelet-derived growth factor (PDGF
) contains two types of subunit, a- and β- PDGFRA
, which are differentially expressed on the cell surface 
binds to three forms of PDGF
and BB) and mediates many biological process including embryonic development, angiogenesis, cell proliferation and differentiation. The role of PDGFRA
in cellular growth and proliferation is underlined by its contribution to the pathogenesis of gastrointestinal stromal tumours 
. A large body of evidence has shown that both PDGF
and its receptors are expressed in corneal epithelium, stromal fibroblasts and endothelium 
as well as proliferative retinal tissues in eyes 
. Along with other cytokines (epidermal growth factor, transforming growth factor-a,-β etc), studies have further suggested that PDGF
and its receptors can mediate corneal fibroblast migration, matrix remodeling and play an important role in corneal wound healing 
. The corneal stroma comprises a large portion of the cornea; the sensitivity of stromal tissue to various growth factors is well described 
. The administration of PDGF
resulted in keratinocyte elongation using rabbit corneal stroma tissue 
. In light of this, a role for PDGFRA
in the regulation of ocular development and parameters cannot be excluded, and our study suggests that genetic polymorphisms within PDGFRA
may be involved in the regulation of corneal biometrics resulting in the occurrence of corneal astigmatism.
In addition, Hammond et al.
reported that 4q12 (MYP9; LOD 3.3) was significant linked with myopia from a genome-wide linkage study of 221 dizygotic twin pairs 
, and subsequent replication revealed nominal significance of 4q12 (P
0.065) for refractive error in African-American families 
. We thus undertook a candidate SNP approach with the identified SNPs to investigate the possible association between PDGFRA
and (i) the onset of high myopia; (ii) the refractive error as a quantitative trait. We did not observe any striking association between the identified variants with either outcomes, suggesting that the association of PDGFRA
with corneal astigmatism is probably not through any shared etiology with myopia.
The lead SNP in our analyses rs7677751 is located in the intro 1 of PDGFRA. Interestingly, among the SNPs identified, rs2228230 is coding-synonymous (valine:GTC>valine:GTT) and resides in exon 18, while rs3690 is within the untranslated-3′ region. These three SNPs (rs7677751, rs2228230 and rs3690) are strongly correlated with each other (pair-wise Pearson correlation coefficient r ranging from 0.77 to 0.81), although the association evidence at the latter two SNPs did not reach genome-wide significance. As the next closest gene (GSX2) from the 5′ end of PDGFRA is 127 kb away and is not within the LD block with our identified SNPs (), it is unlikely that the signals observed in our study are attributed to functional variants located beyond PDGFRA.
Our group recently reported a strong association between variants in PDGFRA
with corneal curvature 
. Corneal curvature is an ocular dimension defined as the average of the radius of corneal curvature at the horizontal and vertical meridians. Myopic eyes have been found to have steeper corneas (reduced radius of curvature), but the significant correlation between corneal curvature and refractive error was not consistently observed 
. Excessively flatter cornea is associated with cornea plana, producing high hyprotropia and likely resulting in angle-closure glaucoma 
. On the other hand, corneal astigmatism is an eye-disorder, where the cornea is more curved in one meridian direction compared to the other. This fragmentizes the light rays entering the eye, leading to the inability to focus onto a single point in the eye 
. It is thus interesting that the same PDGFRA
gene has been identified in two ocular outcomes that are biologically different, given the presence of a weak correlation between corneal astigmatism and corneal curvature (Spearman correlation coefficient r between 0.088 and 0.192 in our cohorts; Figure S6
), pointing to a possible pleiotropic contribution of PDGFRA
Our study has adopted a binary definition of corneal astigmatism (affected and unaffected) that is commonly adopted in clinical practice and eye-trait epidemiology 
. One caveat of this definition is the potential for misclassifying the affected status, particularly for samples with cylinder power around the cutoff threshold of −0.75D. To evaluate the robustness of our findings to the choice of threshold used, we additionally performed the association analysis at the identified SNPs with four different combinations of the thresholds used to define cases and controls. We observed that the odds ratios were highly similar across all four scenarios (Table S3
), with the combined evidence at rs7677751 ranging from Pmeta
. Unsurprisingly, the association evidence was weakest in the scenario with the most stringent thresholding (≤−1.5D for cases and >−0.5 for controls), given this stringency comes at the expense of decreasing the number of individuals in each study. We additionally performed a secondary analysis treating corneal cylinder power as a quantitative trait. Strong statistical evidence was consistently observed at the three leading SNPs (rs7677751, P
; rs2307049, P
and rs7660560, P
; Table S4
), indicating that our findings are robust to the definition of the phenotype.
Owing to the relatively small sample sizes within each of the five GWAS studies, we have chosen to prioritize our survey to identify genetic variants that contribute to the etiology of corneal astigmatism in multiple Asian populations. While Malays have been observed to be genetically closer to the Chinese, the Asian Indians tend to be genetically closer to the Caucasians 
. Our discovery at PDGFRA
thus suggests that part of the underlying biological pathway responsible for astigmatism development is common to multiple populations, although there may be population-specific genetic variants that our current study is not sufficiently powered to identify.
Our study has included two pediatric Chinese populations (SCORM and STARS) with school or pre-school children who are still progressing to their final phenotype. It was documented that a high degree of astigmatism occurs during infancy and the early childhood 
. The prevalence rates remain stable during young adulthood (18 to 40 years), but increase consistently during late adulthood at aged 40 years or older 
. Studies have also indicated that the age-related change in astigmatism is associated with meridians changes in the cornea 
. Children and adolescents have a predominance of “within-the-rule” corneal astigmatism in general, where the vertical curve is greater than the horizontal (axis of 1° to 15°); while in older adults, it shifts to “against-the-rule” astigmatism (axis of 75°–105°) 
. However, our study considers corneal astigmatism without reference to the axis nor the longitudinal changes from children to adults. Whether PDGFRA
plays the same role in pediatric and adults populations will however need further investigation.