All of Us Research Program

Summary

The All of Us Research Program is a longitudinal United States cohort designed to collect health and genomic data from at least one million participants. Its whole-genome sequencing, electronic health records and diverse participant base support replication, multi-ancestry analysis and development of precision-health methods [1].

Role in Metabolic-Flux Validation

Foguet et al. used version 7 whole-genome sequencing and linked records to validate metabolic flux modulation of genetic risk. In 118,058 participants assigned European genetic ancestry, the study identified 14,117 coronary-atherosclerosis cases and 75,204 controls, plus 7,218 myocardial-infarction cases and 86,055 controls.[1]

The validation did not simply compare p-values. It assessed cross-cohort effect correlations, FDR significance and directional agreement. For CAD, 94% of the 583 tested SNP-flux pairs had the same direction as UK Biobank; for MI, 96% of 426 pairs agreed in direction.[1]

Interpretation

The program is intentionally multi-ancestry, but this particular validation was restricted to participants assigned European genetic ancestry to match the discovery analysis. Results from that subset should not be generalized automatically to the entire cohort or to other ancestry groups.

Citations

[1] Foguet et al. (2025), All of Us validation of metabolic flux interactions