Enhancing polygenic risk prediction by modeling quantile-specific genetic effects

Polygenic risk scores (PRSs) quantify an individual's genetic susceptibility to complex traits and diseases. Conventional PRSs, which are based on linear models, perform poorly for phenotypes with skewed distributions or with genetic effects that vary across the distribution. We propose a quantile regression-based PRS (QPRS) that can capture quantile-specific genetic effects. While existing PRSs provide only a single score, QPRS models genetic influences at multiple quantiles of the phenotype, thereby enhancing predictive performance by utilizing these multiple scores as covariates. We evaluate the performance of our method through both simulations and a real-data application. In simulations, QPRS significantly reduces the mean squared error compared to the linear-based PRS, both in the presence of variance quantitative trait loci and outliers. For real data analysis, we use data from Korea Genome and Epidemiology Study to evaluate predictive performance. We consider two prediction tasks: continuous outcomes (triglycerides and glucose level) and a binary outcome (diabetes status, derived from glucose level). QPRS demonstrates consistent improvements over conventional mean-based PRSs across both prediction tasks.