Genome sequencing of 35,024 predominantly African ancestry persons addresses gaps in genomics and healthcare

Genetic variation is crucial in human development, disease susceptibility, and drug response. Despite populations of African descent having the highest degree of genetic variation, genetic research has predominantly focused on populations of European descent, limiting potential for discovery. Recent studies of individuals with African ancestry have driven key medical advances benefiting all populations. Large scale, electronic health record (EHR) linked biobanks have provided opportunities to expand genetic research to larger and more diverse populations. We present initial results from the Alliance for Genomic Discovery (n = 35,024), in which 80% of participants have majority African ancestry, with genome sequencing and extensive phenotyping (median ~10 years of EHR data). We demonstrate that genetic variants known to disproportionately cause disease in patients of African descent are under-documented in the medical record, including treatable genetic conditions such as transthyretin amyloidosis. Our findings confirm that many disease-associated genetic variants have consistent effects between groups with majority African and European ancestry, including common variation, structural variation, and clonal hematopoiesis of indeterminate potential. We discover novel variants associated with drug adverse events and diagnostic codes, powered by the increased frequency of these variants in individuals with majority African ancestry. Furthermore, we report independent effects of genetic risk and social factors on glycemic control in individuals with type 2 diabetes. Overall, this work highlights the value of integrating genome sequencing and deep phenotyping in genetically diverse populations to broaden our understanding of human health and disease. ### Competing Interest Statement Authors from Abbvie, Amgen (and subsidiary deCODE genetics), AstraZeneca, Bayer, BMS, GSK, Illumina, Merck, NashBio, and Novo Nordisk are employees and/or stockholders of their respective institution ### Funding Statement Vanderbilt University Medical Centers BioVU projects are supported by numerous sources: institutional funding, private agencies, and federal grants. These include NIH funded Shared Instrumentation Grant S10OD017985, S10RR025141, and S10OD025092; CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD07471; and additional funding sources listed at https://victr.vumc.org/biovu-funding/. The sequencing of WGS individuals from BioVU, including the 35,024 described here, has been funded by the Alliance for Genomic Discovery consisting of NashBio, Illumina and industry partners Amgen, AbbVie, AstraZeneca, Bayer, BMS, GSK, Merck Sharp & Dohme LLC, and Novo Nordisk. DNA sequencing was performed at deCODE genetics using Illumina sequencing technology. This work was supported by National Institutes of Health (NIH) grants R01HG012657 (Douglas Ruderfer and Lisa Bastarache), U54CA163072 (Jibril Hirbo), RHL174052A and R01HL159557 (Piper Below), T32 HG008341 (Freida Blostein and Cecile Avery), K12AR084232 (Megan Shuey), 5TL1TR002244 (Jeewoo Kim), Merit award 2I01CX001897-06A1 (Adriana M. Hung), ### 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: Institutional Review Board of Vanderbilt University Medical Center gave ethical approval for this work (IRB #240679) 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 This study used data from the Alliance for Genomic Discovery (AGD), a partnership between Nashville Biosciences, Illumina, and Vanderbilt University Medical Center (VUMC). Data access is subject to restrictions and are made available to commercial researchers via NashBio and academic researchers via BioVU. Summary statistics of all results including GWAS and PheWAS are provided publicly here <https://victr.vumc.org/alliance-for-genomic-discovery/>

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