Advancing precision health discovery in a genetically diverse health system
Linking genetic data with electronic health records in hospital biobanks promises to advance precision medicine, but limited ancestral diversity constrains discovery and generalizability. We analyzed 93,936 participants from the UCLA ATLAS Community Health Initiative to inform disease prevalence and genetic risk across five continental and 36 fine-scale ancestry groups. We discovered numerous unreported gene-phenotype associations, including FN3K with intestinal disaccharidase deficiency in Europeans and admixed Americans. Polygenic scores (PGS) robustly predicted common diseases, with effects markedly diminished in non-Europeans. Furthermore, we reduced the pronounced European bias in curated clinical variants using computational predictors, uncovering unreported disease-gene associations, including ANKZF1 and peripheral vascular disease in African Americans. Longitudinal data revealed that semaglutide efficacy varies across ancestries, is associated with PGS for type 2 diabetes, and is modulated by genetic variation in PTPRU. These findings illustrate how ancestrally diverse biobanks from a single health system yield robust disease associations and pharmacogenomic insights.
Authors
- Jaron Arbet (ORCID: https://orcid.org/0000-0003-4218-2458)
- Katelyn J. Queen (ORCID: https://orcid.org/0000-0002-8070-3042)
- Christa Caggiano (ORCID: https://orcid.org/0000-0001-5755-1274)
- Maryam Ariannejad (ORCID: https://orcid.org/0000-0001-9393-6956)
- Timothy S. Chang (ORCID: https://orcid.org/0000-0002-9225-9874)
- Paul Tung
- Michael E. Broudy
- Vishakha Patil
- Ruhollah Shemirani (ORCID: https://orcid.org/0000-0003-1065-7244)
- Takafumi N. Yamaguchi (ORCID: https://orcid.org/0000-0003-1082-3871)
- Lawrence O. Chen
- Danielle B. Martinez
- Yash Patel (ORCID: https://orcid.org/0000-0003-3113-7010)
- Mohammed Faizal Eeman Mootor (ORCID: https://orcid.org/0000-0003-4154-455X)
- Michael Margolis (ORCID: https://orcid.org/0000-0002-3706-8960)
- Tram Tran
- Rupert Hugh-White (ORCID: https://orcid.org/0000-0003-3351-8925)
- Nicole Zeltser (ORCID: https://orcid.org/0000-0001-7246-2771)
- Angela Wei (ORCID: https://orcid.org/0000-0001-6847-9423)
- Shafiul Alam (ORCID: https://orcid.org/0000-0001-8684-624X)
- Sandra Lapinska (ORCID: https://orcid.org/0000-0002-5906-9446)
- Veronica Tozzo (ORCID: https://orcid.org/0000-0001-8538-9198)
- J A Feng
- Roni Haas
- Prapti Thapaliya
- Lora Eloyan
- Alex A.T. Bui
- Paul T. Spellman
- Mao Tian
- Noah Zaitlen
- Daniel H. Geschwind
- Paul C. Boutros
- Bogdan Pasaniuc
- Clara Lajonchere
- Eimear E. Kenny
- Valerie A. Arboleda
Institutions
- Mount Sinai Health System (US)
- University of California, Los Angeles (US)
- UCLA Health (US)
- Los Angeles Medical Center (US)
- New York Genome Center (US)
- University of Pennsylvania (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell
- Published
- 2026-03-01
- DOI
- https://doi.org/10.1016/j.cell.2026.03.007
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00