Multi-omics in the All Of Us Research Program expands mapping genetic mechanisms in health and disease

The All of Us (AoU) Research Program multi-omics cohort was developed to expand discovery of the molecular mechanisms underlying health and disease. Here, we report on the AoU multi-omics cohort comprising proteomic (N = 10,056) and transcriptomic (N = 9,130) sequencing data generated from ancestrally diverse AoU participants. We provide comprehensive expression, splicing, and protein quantitative trait locus (e/s/pQTL) analyses and detected 182,246 QTLs, of which 54,255 finemapped to rare variants and 59.4% (32,235) resolve to a single causal variant. We provide multiple insights into rare variant effects and demonstrate that they are more likely to be ancestrally-restricted, replicate across molecular layers and impact known Mendelian disease genes (OR = 1.4) and approved drug targets (OR = 1.3). Rare variant QTLs from AoU further provided evidence for 5,186 variants, many absent from ClinVar, affecting established disease genes. Combined, the availability of multi-omics in AoU provides a key resource to identify the genetic and molecular mechanisms impacting health and disease across multiple ancestry groups in the United States.