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 = 10,043) 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.
Authors
- Harrison Brand (ORCID: https://orcid.org/0000-0002-7901-0812)
- Joshua Gillard (ORCID: https://orcid.org/0000-0001-8509-2212)
- Jeffrey G. Meyer
- Evin M. Padhi (ORCID: https://orcid.org/0000-0003-2578-2435)
- Sophie Parsa
- Hang Su (ORCID: https://orcid.org/0000-0003-1446-4810)
- Marianne K. DeGorter (ORCID: https://orcid.org/0000-0001-7592-752X)
- Stephen B. Montgomery (ORCID: https://orcid.org/0000-0002-5200-3903)
- Alex L. Yenkin (ORCID: https://orcid.org/0000-0001-5909-7802)
- Yulia Mostovoy (ORCID: https://orcid.org/0000-0002-9544-3538)
- Wail Ba-Alawi (ORCID: https://orcid.org/0000-0002-2747-4703)
- Michael E. Talkowski (ORCID: https://orcid.org/0000-0003-2889-0992)
- Niall J. Lennon (ORCID: https://orcid.org/0000-0002-2874-7371)
- Andrew R. Marderstein (ORCID: https://orcid.org/0000-0003-0859-4969)
- Ashley L. Blegen (ORCID: https://orcid.org/0009-0001-1785-4171)
- Namrata Gupta (ORCID: https://orcid.org/0000-0001-6786-4995)
- Elizabeth A. Kiernan (ORCID: https://orcid.org/0000-0002-6280-6072)
- Mine S. Cicek (ORCID: https://orcid.org/0000-0002-5629-2159)
- Zachary S. Fredericksen
- Konrad J. Karczewski (ORCID: https://orcid.org/0000-0003-2878-4671)
- J. Nguyen (ORCID: https://orcid.org/0009-0009-9156-3186)
- Lee Lichtenstein (ORCID: https://orcid.org/0000-0003-0477-4401)
- Victoria Silva Rosa
- Kiran V. Garimella (ORCID: https://orcid.org/0000-0002-6212-5736)
- Jolene J. Lane
- Victoria A. McNally
Institutions
- Broad Institute (US)
- Mayo Clinic (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-11-01
- DOI
- https://doi.org/10.64898/2026.10.29.26366507
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- preprint
Funders
- Vanderbilt University Medical Center
- Broad Institute
- National Institutes of Health