Disparities in ABO Blood Type Determination Across Diverse Ancestries: A Systematic Review and Validation in the All of Us Research Program

Background: ABO blood types have widespread clinical use and robust associations with cardiovascular disease. Many studies determine ABO blood types using tag single nucleotide polymorphisms (tSNPs) to characterize functional variation. However, tSNPs with low linkage disequilibrium (LD) may promote misinference of ABO blood types, particularly in diverse populations. Methods: Bibliographic databases were searched for studies (2005-2022) using tSNPs to determine ABO alleles in accordance with PRISMA 2020 guidelines. We calculated linkage between tSNPs and functional variants across inferred continental ancestry groups from 1000 Genomes (AFR, AMR, EAS, EUR). We compared r2 across ancestry and assessed real-world consequences by comparing tSNP-derived blood types to serology in a large, diverse population from the All of Us Research Program (AoURP). Results: We observe a lack of phasing and frequent use of inappropriate tSNPs in blood type determination, particularly for O alleles. Linkage between functional variants and O allele tSNPs was significantly lower in African (median r2=0.443) compared to East Asian (r2=0.946, p=1.1×10-5) and European (r2=0.869, p=0.023). In AoURP, discordance between tSNP-derived blood types and serology was high across all SNPs in African ancestry individuals and linkage was strongly correlated with discordance across all ancestries (ρ=-0.90, p=3.08×10-23). Conclusion: We observe common use of inappropriate tSNPs to determine ABO blood type, particularly for O alleles and with some tSNPs mistyping up to 58% of individuals. Our results highlight the lack of transferability of tSNPs across ancestries and potential exacerbation of disparities in genomic research for underrepresented populations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Research reported in this publication was supported by the National Institutes of Health?s National Heart, Lung, and Blood Institute (grants R01 HL156993, R01 HL158686, R21HL172036) and the Office of the Director (grant OT2OD036485). ### 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 study used (or will use) ONLY openly available human data that were originally located at https://workbench.researchallofus.org/ 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 Data from the All of Us Research Program is accessible only through the Researcher Workbench (https://workbench.researchallofus.org/workspaces/aou-rw-a90a6fe4/duplicateofabophewas) as stipulated in the informed consent of participants in the program. This data use agreement prohibits investigators from providing row level data on All of Us participants and thus providing a de-identified dataset is not possible for this manuscript. The code used for this demonstration project is available within the Researcher Workbench. Datasets not generated from the All of Us Research Program and the associated code are available on GitHub (https://github.com/Karnes-Lab/ABO\_systematic\_review). [https://github.com/Karnes-Lab/ABO\_systematic\_review][1] [1]: https://github.com/Karnes-Lab/ABO_systematic_review