Association of polymorphisms in <i>ZFHX1B</i>, <i>KCNQ5</i> and <i>GJD2</i> with myopia progression and polygenic risk prediction in children.

Abstract

To assess the association of single-nucleotide polymorphisms (SNPs) with myopia progression for polygenic risk prediction in children. Six SNPs (<i>ZC3H11B</i> rs4373767, <i>ZFHX1B</i> rs13382811, <i>KCNQ5</i> rs7744813, <i>MET</i> rs2073560, <i>SNTB1</i> rs7839488 and <i>GJD2</i> rs524952) were analysed in 1043 school children, who completed 3-year follow-up, using TaqMan genotyping assays. SNP associations with progression in spherical equivalent (SE) were analysed by logistic regression. Polygenic risk scores (PRS) were applied for computing the sum of the risk alleles of multiple SNPs corresponding to myopia progression, weighted by the effect sizes of corresponding SNPs. <i>GJD2</i> rs524952 showed significant association with fast progression (OR=1.32, 95% CI 1.10 to 1.59; p=0.003) and <i>KCNQ5</i> rs7744813 had nominal association (OR=1.32, 95% CI 1.04 to 1.67; p=0.02). In quantitative traits locus analysis, <i>GJD2</i> rs524952 and <i>KCNQ5</i> rs7744813 were associated with progression in SE (β=-0.038 D/year, p=0.008 and β=-0.042 D/year, p=0.02) and axial elongation (β=0.016 mm/year, p=0.01 and β=0.017 mm/year, p=0.027). <i>ZFHX1B</i> rs13382811 also showed nominal association with faster progression in SE (β=-0.041 D/year, p=0.02). PRS analysis showed that children with the highest PRS defined by rs13382811, rs7744813 and rs524952 had a 2.26-fold of increased risk of fast myopia progression (p=4.61×10^-5). PRS was also significantly associated with SE progression (R²=1.6%, p=3.15×10^-5) and axial elongation (R²=1.2%, p=2.6×10^-4). In this study, multi-tiered evidence suggested SNPs in <i>ZFHX1B</i>, <i>KCNQ5</i> and <i>GJD2</i> as risk factors for myopia progression in children. Additional attention and appropriate interventions should be given for myopic children with high-risk PRS as defined by <i>GJD2</i> rs524952, <i>KCNQ5</i> rs7744813 and <i>ZFHX1B</i> rs13382811.