AI Insight
The All of Us Research Program analyzed proteomic and transcriptomic data from over 10,000 ancestrally diverse participants to identify genetic variants that influence protein and gene expression levels. Researchers detected 182,246 quantitative trait loci (QTLs), with more than half mapping to rare genetic variants, many of which were ancestry-specific and 59.4% resolving to single causal variants. The study found that rare variant QTLs are more likely to affect genes associated with Mendelian diseases and approved drug targets, and identified 5,186 variants affecting disease genes that were largely absent from existing clinical databases.
Why it matters
This resource expands understanding of how rare genetic variants influence molecular mechanisms across diverse populations, potentially improving disease diagnosis and drug development. The identification of thousands of previously uncharacterized variants in disease genes could help resolve cases of unclear genetic diagnoses and identify new therapeutic targets, particularly for underrepresented ancestry groups.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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 = 10,043) and transcriptomic (N = 9,043) 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.