Pan-UK Biobank GWAS improves discovery, analysis of genetic architecture, and resolution into ancestry-enriched effects

Large biobanks, such as the UK Biobank (UKB), enable massive phenome by genome-wide association studies that elucidate genetic etiology of complex traits. However, individuals from diverse genetic ancestry groups are often excluded from association analyses due to concerns about population structure introducing false positive associations. Here, we generate mixed model associations and meta-analyses across genetic ancestry groups, inclusive of a larger fraction of the UKB than previous efforts, to produce freely-available summary statistics for 7,271 traits. We build a quality control and analysis framework informed by genetic architecture. Overall, we identify 14,676 significant loci in the meta-analysis that were not found in the European genetic ancestry group alone, including novel associations for example between CAMK2D and triglycerides. We also highlight associations from ancestry-enriched variation, including a known pleiotropic missense variant in G6PD associated with several biomarker traits. We release these results publicly alongside FAQs that describe caveats for interpretation of results, enhancing available resources for interpretation of risk variants across diverse populations. ### Competing Interest Statement K.J.K. is a consultant for Tome Biosciences, AlloDx, and Vor Biosciences, and a member of the scientific advisory board of Nurture Genomics. M.J.D is a founder of Maze Therapeutics. B.M.N. is a member of the scientific advisory board at Deep Genomics and Neumora. ### Funding Statement This work was supported by the Novo Nordisk Foundation (NNF21SA0072102), NIH grants R37MH107649, R00MH117229, K01MH121659, F31HL167378, and F30AG074507, and BroadIgnite funding. ### 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: This study used data from the UK Biobank. UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval. This approval means that researchers do not require separate ethical clearance and can operate under the RTB approval. 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 All data are available at https://pan.ukbb.broadinstitute.org/, and sample metadata is available in the UK Biobank showcase under return number 2442: https://biobank.ndph.ox.ac.uk/ukb/dset.cgi?id=2442.