Multi-omics in the All Of Us Research Program expands mapping genetic mechanisms in health and disease
- 1Department of Pathology, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA; Department of Biomedical Data S
Abstract
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.
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BibTeX
@misc{padhi2026multiomics,
title = {{Multi-omics in the All Of Us Research Program expands mapping genetic mechanisms in health and disease}},
author = {E. M. Padhi and E. A. Kiernan and J. V. Nguyen and M. K. DeGorter and V. S. Rosa and Y. Mostovoy and A. L. Yenkin and H. Su and L. Lichtenstein and A. R. Marderstein and J. Gillard and W. Baalawi and S. J. Parsa and M. S. Cicek and J. G. Meyer and A. L. Blegen and V. A. McNally and J. J. Lane and Z. S. Fredericksen and All of Us Research Program Multi-omics Working Group and The All of Us Research Program and N. Gupta and H. Brand and K. Garimella and K. J. Karczewski and M. E. Talkowski and N. J. Lennon and S. B. Montgomery},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.29.26366507},
url = {https://www.medrxiv.org/content/10.64898/2026.10.29.26366507v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Multi-omics in the All Of Us Research Program expands mapping genetic mechanisms in health and disease
AU - E. M. Padhi
AU - E. A. Kiernan
AU - J. V. Nguyen
AU - M. K. DeGorter
AU - V. S. Rosa
AU - Y. Mostovoy
AU - A. L. Yenkin
AU - H. Su
AU - L. Lichtenstein
AU - A. R. Marderstein
AU - J. Gillard
AU - W. Baalawi
AU - S. J. Parsa
AU - M. S. Cicek
AU - J. G. Meyer
AU - A. L. Blegen
AU - V. A. McNally
AU - J. J. Lane
AU - Z. S. Fredericksen
AU - All of Us Research Program Multi-omics Working Group
AU - The All of Us Research Program
AU - N. Gupta
AU - H. Brand
AU - K. Garimella
AU - K. J. Karczewski
AU - M. E. Talkowski
AU - N. J. Lennon
AU - S. B. Montgomery
PY - 2026
DA - 2026/10/29
PB - medRxiv
DO - 10.64898/2026.10.29.26366507
UR - https://www.medrxiv.org/content/10.64898/2026.10.29.26366507v1
AB - 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.
ER -