Diverse Genomes, Shared Health: Insights from a Health System Biobank

Summary 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 AFR. 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. Competing Interest Statement E.E.K. has received personal fees from Regeneron Pharmaceuticals, 23&Me, Allelica, and Illumina; has received research funding from Allelica; and serves on the advisory boards for Encompass Biosciences, Overtone, and Galateo Bio. P.T.S. is a consultant for 10X Genomics, Illumina, Foresight Diagnostics, Natera, and Twinstrand. P.C.B. sits on the Scientific Advisory Board of Intersect Diagnostics Inc. and previously sat on those of Sage Bionetworks and BioSymetrics Inc. All other authors declare no conflict of interest. Funding Statement We are deeply grateful to the participants of the UCLA Health Biobank, to the DGSOM and UC Health for their support and development of ATLAS, and to Allen and Charlotte Ginsburg for their support of the UCLA Institute for Precision Health, which oversees ATLAS. WES data for this study were generated as part of the partnership of UCLA Health with Regeneron Genetics Center (RGC). R.H. was supported by EMBO Postdoctoral Fellowship ALTF 1131-2021 and the Prostate Cancer Foundation Young Investigator Award 22YOUN32. M.P.M. was supported by the UCLA-Caltech Medical Scientist Training Program (T32-GM008042) and by the National Institute of Mental Health (F30-MH135712). A.W. was supported by the National Human Genome Research Institute (F31-HG013462). J.F. was supported by the National Institute of Biomedical Imaging and Bioengineering Medical Imaging Informatics Training Grant (T32-EB016640). D.H.G., P.C.B., A.A.T.B. and C.L. were supported by UCLA CTSI. T.S.C. was supported by NIH grants K08AG065519-01A1, R01AG085518-01A1, U54NS123746 and California Department of Public Health, Chronic Disease Control Branch, Alzheimer's Disease Program, under Contract #22-10079 and #24-10127. N.Zeltser. was supported by the National Human Genome Research Institute (T32-HG002536) and by the National Cancer Institute (F31-CA281168). V.A.A. and N.Zaitlen. are supported by the National Human Genome Research Insitute-R01HG011345. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of the University of California Los Angeles gave ethical approval for this work. The IRB Number for the ATLAS Initiative protocol is IRB#17-001013. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Data Availability Due to privacy regulations/legal restrictions within the Health System and licensing terms, individual-level data cannot be published. Comprehensive processed data and summary statistics are available in the supplementary tables or through our browser (atlas-phewas.mednet.ucla.edu). Access to individual-level data may be possible through collaborative efforts and meta-analysis. This paper does not report original code.