Whole-genome sequencing (WGS) provides a comprehensive view of the genome, enabling detection of coding and non-coding genetic variation, and surveying complex regions which are difficult to genotype. Here, we report on whole-genome sequencing of 490,640 UK Biobank participants, building on previous genotyping1 and whole-exome sequencing (WES) efforts2,3. This advance deepens our understanding of how genetics influences disease biology and further enhances the value of this open resource for the study of human biology and health. Coupling this dataset with rich phenotypic data, we surveyed within- and cross-ancestry genomic associations with health-related phenotypes and identified novel genetic and clinical insights. While most genome-wide significant associations with disease traits were primarily observed in Europeans, we also identified strong or novel signals in individuals of African and Asian ancestries. Deeper capture of exonic variation in both coding and UTR sequences, strengthened and surfaced novel insights relative to WES analyses. This landmark dataset, representing the largest collection of WGS and available to the UK Biobank research community, will enable advances into our understanding of the human genome, and facilitate the discovery of new diagnostics, therapeutics with higher efficacy and improved safety profile, and enable precision medicine strategies with the potential to improve global health.

The authors have declared no competing interest.

This study was funded by This research has been conducted with the support of Wellcome (grant nos. 218880/Z/19/Z to Amgen, 218723/Z/19/Z to AstraZeneca, 218789/Z/19/Z to GSK, 219414/Z/19/Z to Janssen and 219603/Z/19/Z to UK Biobank), UK Research and Innovation (Innovate UK grant nos. 105637 to Amgen, 105635 to AstraZeneca, 105634 to GSK and 105636 to Janssen), Medical Research Council award for Vanguard programme (grant no. MC_PC_17223).

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:

Ethics committee/IRB of The North West Research Ethics Committee gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 are available online at WGS data can be accessed via the UK Biobank research analysis platform (RAP): https://ukbiobank.dnanexus.com/landing. The Research Analysis Platform is open to researchers who are listed as collaborators on UKB-approved access applications. Allele frequency browser is available at https://afb.ukbiobank.ac.uk/. Rare variant collapsing analysis association statistics are available through the AstraZeneca Centre for Genomics Research (CGR) PheWAS Portal (http://azphewas.com/). SV association data is available at https://www.decode.com/summarydata/. Human reference genome GRCh38, http://ftp.1000genomes.ebi.ac.uk/vol1/ftp/technical/reference/GRCh38_reference_genome/. GIAB WGS samples https://ftp-trace.ncbi.nlm.nih.gov/ReferenceSamples/giab/data/ ENSEMBL https://m.ensembl.org/info/data/mysql.html .

https://ukbiobank.dnanexus.com/landing