Genome-wide association study identified novel loci and gene-environment interaction for refractive error in children

Abstract

To identify novel genetic loci for children refractive error, we performed a meta-analysis of two genome-wide association studies (GWASs) of spherical equivalent (SE) in 1,237 children from the population-based Hong Kong Children Eye Study (HKCES) and the Low Concentration Atropine for Myopia Progression (LAMP) study. Replication was conducted in 4,093 Chinese children and 1,814 Chinese adults. Four lead-SNPs (MIR4275 rs292034, TENM3 rs17074027, LOC101928911 rs6925312 and FAM135B rs4609227) showed genome-wide significant association (P ≤ 5.0 × 10^-8) with SE. TENM3 had been associated with myopia in adults before, whilst the other three loci, MIR4275, LOC101928911 and FAM135B, were novel. Significant interaction between genetic risk scores (GRS) and near work on SE was also detected (β_interaction = 0.14, P_interaction = 0.0003). This study identified novel genetic loci for children refractive error and suggested myopia intervention can be individualized based on the genetic risk of children.

Fig. 1. Meta-analysis results for genome-wide association to spherical equivalent in discovery stage.

The y axis is –log10 P values for association with spherical equivalent, the x axis is chromosomes and base pair positions based on human genome build 37. The horizontal red and blue lines indicate genome-wide significance (P ≤ 5.0 × 10⁻⁸) and candidate significance (P ≤ 1.0 × 10⁻⁵), respectively. The figure was generated using R package (v. 3.4.2).

Fig. 2. The effects of GRS and diopter-hours on myopia.

a Interactions between GRS and diopter-hours on SE. The scatter plot represents estimated individuals’ daily diopter-hours and their corresponding SE. Each line represents the linear regression between diopter hours and SE for each stratum of GRS. b The odds ratio of myopia across strata of diopter-hours and GRS. Each point represents an odds ratio estimate and the vertical lines indicating confidence intervals. The blue, green and pink labels indicate low, moderate, and high GRS strata, respectively. The dashed horizontal line at 1.0 represents the null effect. GRS, genetic risk score; SE, spherical equivalent. The figure was generated using R package (v. 3.4.2).