Prospective Analysis of Incident Disease among Individuals of Diverse Ancestries Using Genetic and Conventional Risk Factors

Background Human genetics provides opportunities for enhancing disease prediction through polygenic risk scores (PRS). Method We used a dataset from 23andMe (6.77M European, 1.30M Latine, and 0.45M African American individuals). Using cross-sectional data for PRS construction and a prospective cohort for evaluation, we estimated PRS-associated cumulative incidences after one year of follow-up for 12 clinical endpoints. Results The cumulative incidence of disease at one year was consistently higher among individuals in the top 10% of each PRS. Relative risks (RRs) comparing top to bottom 10% of PRS differed across diseases (e.g. European RR 2.12 for eczema vs 12.53 for T2D). Estimates were similar between Europeans and Latines however were more modest for African Americans (e.g. T2D RR 10.92 for Latines vs. 4.00 for African Americans). Clinical manifestation occurred earlier among those in top vs bottom 10% of polygenic risk: 16yrs for hypertension, and 9.5yrs for T2D. Among participants at elevated conventional risk of CHD or T2D, those in the top 10% PRS had a 10-20 fold higher RR of disease incidence vs those not at conventional risk. Among individuals at high polygenic risk of CHD or T2D, favorable lifestyle characteristics associated with 64-73% lower RR of developing disease over 1-year, with cumulative incidence equivalent to the population average. Conclusion In an ancestrally-diverse cohort, individuals in the top 10% PRS had higher 1-year disease incidence and earlier age of clinical manifestation. PRS provided risk stratification beyond conventional risk factors. Lifestyle characteristics markedly lowered disease incidence among those at elevated polygenic risk.