A comprehensive exploration of the impact and contribution of polygenic risk score on age at onset of 30 complex diseases

Objectives

Polygenic risk score (PRS) has increasingly shown promise in predicting disease risk; however, studies examining the influence of PRS on age at onset remain limited. This study aimed to systematically assess the impact of PRS on age at onset across multiple diseases.

Study design

Prospective cohort study

Methods

We calculated PRS with two methods (C+T and PRS-CS) and compared their predictive capability in age at onset of 30 diseases in the UK Biobank. We next evaluated the effect of PRS on age at onset and quantified the influence of PRS on disease risk across early and late onset cases.

Results

PRS-CS behaved better in predicting age at onset of most diseases (except for Alzheimer's disease) compared to C+T. Higher PRS was associated with earlier age at onset for 23 diseases, with the average age at onset advanced by 1.94 years. Compared to women, men faced an advanced onset for 5 diseases. Compared to average PRS (20–80 %), individuals in the top 2.5 % of the PRS distribution displayed a significantly earlier age at onset for 19 diseases, ranging from 2.85 (1.68–4.03) years advancement for gout to 13.70 (9.88–17.52) years advancement for Crohn's disease. Compared to the late-onset group, the early-onset group exhibited a greater onset risk in 21 diseases, with the early-onset risk of colon cancer being 2.78-fold higher than the late-onset risk (OR = 11.42 [9.77–12.45] vs. 3.95 [3.85–4.06], P < 0.001).

Conclusions

Higher PRS generally leads to earlier age at onset, which supports the potential role of PRS in screening high early-onset risk individuals susceptible to chronic diseases.