Yield of genetic association signals from genomes, exomes, and imputation in the UK biobank

Whole genome sequencing (WGS), whole exome sequencing (WES), and array genotyping with imputation (IMP) are common strategies for assessing genetic variation and its association with medically relevant phenotypes. To date there has been no systematic empirical assessment of the yield of these approaches when applied to 100,000s of samples to enable discovery of complex trait genetic signals. Using data for 100 complex traits in 149,195 individuals in the UK Biobank, we systematically compare the relative yield of these strategies in genetic association studies. We find that WGS and WES combined with arrays and imputation (WES+IMP) have the largest association yield. While WGS results in a ∼5-fold increase in the total number of assayed variants over WES+IMP, the number of detected signals differed by only 1% for both single-variant and gene-based association analyses. Since WES+IMP typically results in savings of lab and computational time and resources expended per sample, we evaluate the potential benefits of applying WES+IMP to larger samples. When we extend our WES+IMP analyses to 468,169 UK Biobank individuals, we observe a ∼4-fold increase in association signals with the ∼3-fold increase in sample size. We conclude that prioritizing WES+IMP and large sample sizes, rather than current short-read WGS alternatives, will maximize the number of discoveries in genetic association studies. ### Competing Interest Statement All authors are current employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. ### Funding Statement This study was funded by the Regeneron Genetics Center which is a subsidiary of Regeneron Pharmaceuticals. ### 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 Individual-level genotyping array and sequencing data that have been deposited with the UK Biobank and are freely available to approved researchers. Individual-level phenotype data used are also available to approved researchers for the surveys and health-record datasets from which all of our traits are derived. Instructions for access to UK Biobank data are available at . 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 produced in the present work are contained in the manuscript