Systematic single-variant and gene-based association testing of thousands of phenotypes in 426,370 UK Biobank exomes

Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variation in human disease has not been explored at scale. Exome sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variation across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 4,529 phenotypes using single-variant and gene tests of 426,370 individuals in the UK Biobank with exome sequence data. We find that the discovery of genetic associations is tightly linked to frequency as well as correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside the Genebass browser for rapidly exploring rare variant association results. ### Competing Interest Statement KJK is a consultant for Vor Biopharma. BRG, XZ, FR, SE, AJG, MR, JW, HJ, JWD are employees of AbbVie Inc. MR is an employee of and owns stock in AbbVie Inc. EAT, DS, PGB, HR are employees of Biogen and hold stocks/stock options in Biogen. HK, XC, XH and MRM are employees of Pfizer. DK holds stock in the private company TriNetX, LLC. DSP was an employee of Genomics plc. All the analyses reported in this paper were performed as part of DSP's previous employment at the Massachusetts General Hospital and Broad Institute. NAW owns stock in Pfizer. LDG receives funding from Intel and Illumina. DGM is a founder with equity of Goldfinch Bio, and serves as a paid advisor to GSK, Variant Bio, Insitro, and Foresite Labs. HLR is a member of the scientific advisory board at Genome Medical. AAP is a Venture Partner at GV. He has received consulting fees from Novartis, and receives funding from Bayer, IBM, Microsoft, Alphabet, Intel, GSK, Pfizer, Illumina. MJD is a founder of Maze Therapeutics. BMN is a member of the scientific advisory board at Deep Genomics and RBNC Therapeutics, member of the scientific advisory committee at Milken and a consultant for Camp4 Therapeutics, Merck and Biogen. ### Funding Statement This work was funded by Abbvie, Biogen, and Pfizer, who are represented by co-authors on this manuscript ### 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: UK Biobank applications 26041 and 48511 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data is publicly available at