Variance Polygenic Scores (vPGS) as a Tool for Studying Gene-Environment Interactions Associated With Refractive Error

Abstract

Abstract Purpose Conventional polygenic scores predict an individual’s phenotype based on their genetics. By contrast, variance polygenic scores (vPGS) quantify genetic predisposition to phenotypic variance. We tested the hypothesis that a vPGS for refractive error can identify individuals with increased susceptibility to environmental risk factors for myopia. Methods Six vPGS construction strategies were evaluated in UK Biobank participants: three variance heterogeneity genome-wide association studies (vGWAS) methods and two reweighting schemes. vPGS performance was assessed using two metrics: (i) ‘Diff’ – difference in phenotypic variance in vPGS decile one vs. ten; (ii) Spearman correlation of phenotypic variance vs. vPGS decile. The optimal vPGS was used to test for vPGS × time spent reading or vPGS × time spent outdoors interactions in children aged 15 years (ALSPAC cohort; n=3471). Results Of the vGWAS methods, conditional quantile regression outperformed SCAMPI and Levene’s Test. Of the re-weighting schemes, LDpred2 outperformed pruning and thresholding (P+T). In an independent sample of UK Biobank participants (n=19470), the top-performing vPGS successfully stratified individuals into groups with increasing variance in refractive error, even after adjusting for a conventional PGS (Diff: 2.55, 95% CI: 1.64–3.47; Spearman correlation: 0.87, 95% CI: 0.43–0.93). However, in ALSPAC participants, there was minimal support for vPGS interactions with time reading (P=0.80) or time outdoors (P=0.89). Conclusion A novel vPGS successfully stratified individuals into groups with relatively high or low genetic susceptibility to refractive error variance. However, the vPGS could not identify individuals at enhanced risk from lifestyle risk factors for myopia.