Polygenic Risk Prediction Identifies Genetic Myopia Risk

Ophthalmologist gesturing to girl while wearing protective face mask. Female child is sitting behind optometry in doctor’s office. They are in hospital for eye exam during COVID-19 crisis.
Researchers advocate for genetic screening of patients with risk factors.

Genetic screening and additional interventions should be provided to children who have myopia and are at high polygenic risk for single-nucleotide polymorphisms (SNPs), according to research results published in the British Journal of Ophthalmology. The study identified SNP in 3 particular genes: GJD2, KCNQ5, and ZFHX1B.

Researchers sought to evaluate the relationship and polygenic risk score of 6 single-nucleotide polymorphisms (SNPs; ZC3H11B rs4373767, ZFHX1B rs11382811, KCNQ5 rs7744813, MET rs2073560, SNTB1 rs7839488, and GJD2 rs523952) in 6 genes with the progression of myopia in a cohort of children in Hong Kong. Participants were between 6 and 8 years of age, enrolled in the ongoing, population-based Hong Kong Children Eye Study (HKCES) and completed 3 years of follow-up by December 2019. 

The cohort included 1043 children (mean age, 7.50±-0.80 years; 50.1% boys), with comparable baseline demographics to the HKCES cohort as a whole. Children had no additional treatment other than refractory lenses during the 3-year study period. During the study period, progression rate was -0.41±0.34 D per year for spherical equivalent and 0.26±0.14 mm per year for axial length. 

Compared with slow progression, KCNQ65 rs7744813 demonstrated a nominal association with fast progression (odds ratio [OR], 1.32; 95% CI, 1.04-1.67), while GJD2 rs524952 was associated significantly with fast progression and a T allele that conferred a 1.32-fold increased risk towards fast progression once adjusted for sex and age (OR, 1.32; 95% CI, 1.10-1.59). 

Following adjustments for age, gender, near work, and time spent outdoors, the associations between KCNQ5 rs7744813 and GJD2 rs52952 with fast progression remained. The other 4 gene SNPs did not demonstrate a significant association, although a trend was noted with ZFHX1B rs13382811 towards fast progression (OR, 1.19; 95% CI, 0.96-1.48). 

Participants were also divided into quintiles based on spherical equivalent progression rates. In comparing Q4 with Q1 (fastest progression vs slowest progression), SNPs ZFHX1B rs13382811 and GJD2 rs524952 (ORs, 1.51 and 1.32, respectively) were associated with an increased risk of fast progression. A trend test further compared the relationship between these 2 specific SNPs and fast myopia progression. 

SNPs demonstrated differential associations with spherical equivalent at baseline, spherical equivalent at 3-year follow-up, and progression of spherical equivalent. KCNQ5 rs7744813 demonstrated a significant association at baseline with spherical equivalent (β=-0.24), while MET rs20733560 and GJD2 rs524952 demonstrated borderline and nonsignificant associations, respectively. 

GJD2 rs524952 was significantly associated with myopia progression (β=0.038 D/year), compared with KCNQ5 rs7744813 which showed a “nominal” association. 

A polygenic risk score model with ZFHX1B rs13382811, KCNQ5 rs7744813, and GJD2 rs524952 showed the lowest P value and best fitness among all models (R2=2.2%; P =5.44×10-5), and in the quintile strata, highest polygenic risk scores indicated significant association with myopia progression compared with the reference quintile (ORs 1.92; 95% CI, 1.24-2.97; P =.0011 and OR, 2.26, 95% CI, 1.50-3.42; P =4.61×10-5, respectively). 

Study limitations include the use of only 2 refraction measurements at each timepoint, a lack of annual data on myopia progression, the selection of only 1 representative SNP in each gene, and the generation of only “nominally significant” P values for 2 SNPs. 

“We have identified [the] association of SNPs in 3 genes, ZFHX1B, KCNQ5, and GJD2, with faster myopia progression in Chinese children,” the research shows. “Our findings provide evidence for the need of genetic screening in myopic children. Those having the highest [polygenic risk scores] defined by the 3 gene SNPs should be given appropriate intervention to slow myopia progression.  


Chen LJ, Li FF, Lu SY, et al. Association of polymorphisms in ZFHX1B, KCNQ5, and GJD3 with myopia progression and polygenic risk prediction in children. Published online April 2, 2021. Br J Ophthalmol. doi:10.1136/bjophthalmol-2020-318708