Serum Urate Polygenic Risk Score Can Improve Gout Risk Prediction: A Large-Scale Cohort Study

Gout is a painful inflammatory arthritis affecting more than 8 million Americans. Identifying high-risk patients in early life could potentially encourage people to adopt lifestyle changes to prevent gout. Polygenic risk score (PRS) provides an overall estimate of an individual's genetic liability to develop a disease and can be used for early identification of high-risk individuals. In this study, we validated a previously reported PRS in an independent cohort. The urate-PRS was constructed from 110 significant urate-associated variants identified in Europeans. Phenome-wide and PRS-wide association study showed the urate-PRS is highly specifically associated with gout (phecode: 274.10; beta = 1.495 [1.372, 1.619], p = 4.37e-124). Urate-PRS alone did not performed in the gout prediction (area under the receiver operating characteristic curve, AUROC = 0.640); however, the addition of PRS upon demographics significantly improved the model performance, yielding an AUROC of 0.804 from 0.777 (DeLong test p = 3.66e-9). Trans-ethnic PRS and European-specific PRS showed similar prediction performance. We observed increasing gout prevalence and odds ratio (OR) across the PRS quintiles. Our study showed 8.2% of the cohort had more than 2.5 odds for gout than remainders, indicating that urate-PRS may be a better marker than age and sex to stratify patient risk. With the rapid growth of large biorepositories, such as All of Us, urate-PRS can be applied quickly and widely in population to estimate individual's risk, providing a powerful tool for gout preventive purpose in population health.