An unbiased comparison of 14 epigenetic clocks in relation to 10-year onset of 174 disease outcomes in 18,859 individuals.

Epigenetic Clocks have been trained to predict chronological age, healthspan and lifespan. Such clocks are often analysed in relation to disease outcomes - typically using small datasets and a limited number of clocks. Here, we present the first large-scale (n=18,849), unbiased comparison of 14 widely used clocks as predictors of 174 incident disease outcomes and all-cause mortality. Second-generation clocks significantly outperformed first-generation clocks, which have limited applications in disease settings. Of the 176 Bonferroni significant (P<0.05/174) associations, there were 27 diseases (including primary lung cancer and diabetes) where the hazard ratio for the clock exceeded the clock's association with all-cause mortality. Furthermore, there were 35 instances where adding a clock to a null classification model with traditional risk factors increased the classification accuracy by >1% with an AUCfull > 0.80. Second-generation epigenetic clocks show promise for disease risk prediction, particularly in relation to respiratory and liver-based conditions.