Education influences the association between genetic variants and refractive error: A meta-analysis of five Singapore studies

Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay. Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor, education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education (SHISA6-DNAH9: rs2969180 A allele, β = -0.33 D, P = 3.6 × 10^-6; GJD2: rs524952 A allele, β = -0.31 D, P = 1.68 × 10^-5; ZMAT4-SFRP1: rs2137277 A allele, β = -0.47 D, P = 1.68 × 10^-4), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82 × 10^-3-4.78 × 10^-4). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 × 10^-8), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene-environment interactions in the pathophysiology of myopia.