Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development

A genetic contribution to refractive error has been confirmed by the discovery of more than 150 associated variants in genome-wide association studies (GWAS). Environmental factors such as education and time outdoors also demonstrate strong associations. Currently however, the extent of gene-environment or gene-gene interactions in myopia is unknown. We tested the hypothesis that refractive error-associated variants exhibit effect size heterogeneity, a hallmark feature of genetic interactions. Of 146 variants tested, evidence of non-uniform, non-linear effects were observed for 66 (45%) at Bonferroni-corrected significance (P？<？1.1？×？10？4) and 128 (88%) at nominal significance (P？<？0.05). LAMA2 variant rs12193446, for example, had an effect size varying from ？0.20 diopters (95% CI ？0.18 to ？0.23) to ？0.89 diopters (95% CI ？0.71 to ？1.07) in different individuals. SNP effects were strongest at the phenotype extremes and weaker in emmetropes. A parsimonious explanation for these findings is that gene-environment or gene-gene interactions in myopia are pervasive