Abstract
BACKGROUND: The polygenic risk score (PRS) has been perceived as advantageous in predicting the risk of complex diseases compared to other measures. We aimed to systematically evaluate the influence of PRS on disease outcome and to explore its predictive value. METHODS: We comprehensively assessed the relationship between PRS and 32 complex diseases in the UK Biobank. We used Cox models to estimate the effects of PRS on the incidence risk. Then, we constructed prediction models to assess the clinical utility of PRS in risk prediction. For 16 diseases, we further compared the disease risk and prediction capability of PRS across early and late-onset cases. RESULTS: Higher PRS led to greater incident risk, with hazard ratio (HR) ranging from 1.07 (95% confidence interval (CI) = 1.06-1.08) for panic/anxiety disorder to 4.17 (95% CI = 4.03-4.31) for acute pancreatitis. This effect was more pronounced in early-onset cases for 12 diseases, increasing by 52.8% on average. Particularly, the early-onset risk of heart failure associated with PRS (HR = 3.02; 95% CI = 2.53-3.59) was roughly twice compared to the late-onset risk (HR = 1.48; 95% CI = 1.46-1.51). Compared to average PRS (20-80%), individuals positioned within the top 2.5% of the PRS distribution exhibited varying degrees of elevated risk, corresponding to a more than five times greater risk on average. PRS showed additional value in clinical risk prediction, causing an average improvement of 6.1% in prediction accuracy. Further, PRS demonstrated higher predictive accuracy for early-onset cases of 11 diseases, with heart failure displaying the most significant (37.5%) improvement when incorporating PRS into the prediction model (concordance index (C-index) = 0.546; standard error (SE) = 0.011 vs. C-index = 0.751; SE = 0.010, P = 2.47 × 10(-12)). CONCLUSIONS: As a valuable complement to traditional clinical risk tools, PRS is closely related to disease risk and can further enhance prediction accuracy, especially for early-onset cases, underscoring its potential role in targeted prevention for high-risk groups.