and J.M. This software is licensed free for use by researchers at academic institutions. Results (P values) of association tests between human height and genotypes using three different sets of data for chromosome 2. A reference panel of 64,976 haplotypes for genotype imputation. The markers with very different allele frequencies seen on the top, bottom and left-hand sides of the plot comprise approximately 300 markers. Further details of the array design are in the UK Biobank Axiom Array Content Summary2. Sudlow, C. et al. 42, D1001–D1006 (2014). 12, 581–594 (2013). In a separate experiment that leveraged phase inferred from mother–father–child trios, we estimated a median phasing switch error rate of 0.229% (see Methods). We analysed 409,724 individuals in the white British ancestry subset (see Methods) and focused on 11 self-reported immune-mediated diseases with known HLA associations. Nat. The BGEN library source code is available at https://bitbucket.org/gavinband/bgen. The UK Biobank resource with deep phenotyping and genomic data Clare Bycroft. Robust relationship inference in genome-wide association studies. 2). Online resources are being developed for sharing the results of analyses using UK Biobank data, including the release of GWAS results for thousands of phenotypes (http://www.nealelab.is/uk-biobank) and the Oxford Brain Imaging Genetics server28 (http://big.stats.ox.ac.uk/). In 2019, the UK Biobank (UKB) released whole-exome sequences of 50,000 UKB participants, providing the unique opportunity to link genetic information of a large community-dwelling cohort to individual health records and neuroimaging data. These filters resulted in a dataset with 670,739 autosomal markers in 487,442 samples. Affymetrix applied a custom genotype calling pipeline and quality filtering optimized for biobank-scale genotyping experiments and the novel genotyping arrays, which contain markers that had not been previously typed using Affymetrix technology (see Methods). For samples of European ancestry, the estimated four-digit accuracy for the maximum posterior probability genotype is above 93.9% for all 11 loci (Supplementary Table 7). The genetic and phenotype datasets generated by UK Biobank analysed during the current study are available via the UK Biobank data access process (see http://www.ukbiobank.ac.uk/register-apply/). http://creativecommons.org/licenses/by/4.0/, https://doi.org/10.1038/s41586-018-0579-z, Risk of Coronary Artery Disease Conferred by Low-Density Lipoprotein Cholesterol Depends on Polygenic Background, The associations of plasma phospholipid arachidonic acid with cardiovascular diseases: A Mendelian randomization study, Selective Serotonin Reuptake Inhibitor Pharmaco-Omics: Mechanisms and Prediction, Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19, Single-cell genomics to understand disease pathogenesis. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O'Connell J, Cortes A, Welsh S, Young A, Effingham M, McVean G, Leslie S, Allen N, Donnelly P, Marchini J. PLoS Genet. The number of markers we analysed in the UK Biobank (768,502) is considerably more than in GIANT (106,263), and this affects the resolution of any given associated region (Extended Data Fig. Shibata, K. et al. and M.E. 3, 769–781 (2015). This pipeline was applied to all samples, including the 150,000 samples that were part of the interim data release. This analysis used 91,298 overlapping markers. It is likely to herald a new era in which these and related resources drive and enhance understanding of human biology and disease. An information score of α in a sample of M individuals indicates that the amount of data at the imputed marker is approximately equivalent to a set of perfectly observed genotype data in a sample size of αM. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. The UK Biobank resource with deep phenotyping and genomic data Bycroft, C et al. 69, 823–836 (2017). The result of the imputation process is a dataset with 93,095,623 autosomal SNPs, short indels and large structural variants in 487,442 individuals. Thank you for visiting nature.com. The SNP database (dbSNP) reference SNP (rs) IDs were assigned to as many markers as possible using reference SNP ID lists available from the UCSC genome annotation database for the GRCh37 assembly of the human genome (http://hgdownload.cse.ucsc.edu/goldenpath/hg19/database/). We called relationship classes for each related pair using the kinship coefficient and fraction of markers for which they share no alleles (IBS0). The UK Biobank. 1). There are 652 samples with a probable sex chromosome aneuploidy (indicated by crosses). We use cookies to ensure that we give you the best experience on our website. This could be due to non-working probesets on the UK Biobank arrays or possibly annotation error on the UK Biobank arrays or in ExAC, or mapping errors in the sequence data in regions of more complex variation. There were 16,443,622 such markers in UK Biobank imputed data, 703,946 in the UK Biobank genotyped data, and 2,546,872 in GIANT. A haplotype map of the human genome. There were only three windows contained in UK Biobank genotyped data and not the imputed data. 2 Examples of intensity data and genotype calls for markers of different allele frequencies. b, The distribution of the number of batch-level quality control (QC) tests that a marker fails (see Methods). Neurosci. In all cases these were consistent with previous reports (see Methods and Supplementary Table 9). Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK, The UK Biobank resource with deep phenotyping and genomic data, Scientific animation | Scientists closer to finding the cell of origin for ovarian cancer, Unleashing the Potential of a Diverse Workforce, Centre Director featured in “Talking Machines” podcast, Risk Assessments, Appendices & Other Info. Nature thanks E. Banks, M. Boehnke, B. Pasaniuc, D. MacArthur and the other anonymous reviewer(s) for their contribution to the peer review of this work. The vertical line shows the threshold we used to call samples as outliers on missing rate. One of the major strengths of UK Biobank is the wide range of information collected on all 500,000 participants. Measurements for a wide range of biochemical markers of key interest to the research community have also been carried out, including those that have known associations with disease (for example, lipids for vascular disease and sex hormones for cancer), diagnostic value (for example, HbA1c for diabetes and rheumatoid factor for arthritis), or the ability to characterize phenotypes not otherwise well assessed (for example, biomarkers for renal and liver function). Nature. Genotypes Numbers indicate the approximate count of markers within each category, ignoring any overlap. The two markers with the smallest P value for each of the genotyped data and imputed data are enlarged and highlighted with black outlines, and other UK Biobank markers are coloured according to their correlation (r2) with one of these two. This software is currently licensed free for use by researchers at academic institutions. ... deep phenotyping data . Extended Data Fig. Participants reported their ethnic background by selecting from a fixed set of categories14. As would be expected under Hardy–Weinberg equilibrium, there are no instances of samples with the minor homozygote genotype. We used PCA to measure population structure within the UK Biobank cohort (see Methods). 4 Distribution of information scores at autosomal markers in the imputed dataset. Nielsen, J. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. We alleviated this effect by only using a subset of markers that are only weakly informative of ancestral background (Supplementary Information, Supplementary Fig. Nat. Nature 476, 214–219 (2011). Z-scores were calculated as effect size divided by standard error, but only for markers with P < 5 × 10−8 in GIANT, for a set of 575 associated regions, which we also used for the credible set analysis (see Methods). UKB_WCSGAX: UK Biobank 500K Samples Genotyping Data Generation by the Affymetrix Research Services Laboratory http://biobank.ndph.ox.ac.uk/showcase/docs/affy_data_generation2017.pdf (2017). PubMed Google Scholar. To facilitate its wider use, we applied a range of quality control procedures and conducted a set of analyses that reveal properties of the genetic data—such as population structure and relatedness—that can be important for downstream analyses. Affymetrix. b, c, Both plots are from the analysis considering all markers in each study. If there is exactly one causal marker in the region and genotypes for that marker are available in the data, then the posterior probability that a marker i drives the association signal in the region r is given by: where BFkr is the Bayes factor for marker i in the r region33. The inset shows rare markers only (MAF < 0.01). See Extended Data Table 1 for more details. From Wikipedia, the free encyclopedia UK Biobank is a large long-term biobank study in the United Kingdom (UK) which is investigating the respective contributions of genetic predisposition and environmental exposure (including nutrition, lifestyle, medications etc.) Subsequent to the interim release of genotypes (May 2015) for approximately 150,000 UK Biobank participants improvements were made to the genotype calling algorithm35 and quality control procedures. Wood, A. R. et al. 4e). Each point represents one sample and is coloured according to the inferred genotype at the marker. We also conducted quality control specific to the sex chromosomes using a set of 15,766 high quality markers on the X and Y chromosomes. Accounting for the ancestral background is essential both for epidemiological studies and genetic analyses, such as GWAS19. Countries (rows) have been ordered using hierarchical clustering (‘hclust’ function in R). Phasing on the autosomes was carried out using SHAPEIT324 (see Methods and https://jmarchini.org/software/). The sample processing and genotyping was supported by the National Institute for Health Research, Medical Research Council, and British Heart Foundation. The marker content of the UK Biobank Axiom array was chosen to capture genome-wide genetic variation (single nucleotide polymorphism (SNPs) and short insertions and deletions (indels)), and is summarized in Fig. Nat. Webb, T. R. et al. PLoS Med. Below you will find all the published papers using UK Biobank data. These were assayed using two very similar genotyping arrays. Haplotype estimation and genotype imputation was carried out on the two pseudo-autosomal regions and the non-pseudo autosomal region separately, and using the same methods and reference datasets used for the autosomes. All plots show properties of the UK Biobank genotype data after applying quality control. Genome-wide genotyping was performed on all UK Biobank participants using the UK Biobank Axiom Array. This file contains Supplementary Material, including Supplementary Figures S1-S18 and Supplementary Tables S1-S13. 2, for markers of interest using a utility such as Evoker (https://github.com/wtsi-medical-genomics/evoker), especially for rare markers. A total of 147,731 UK Biobank participants (30.3%) are inferred to be related (third degree or closer) to at least one other person in the cohort, and form a total of 107,162 related pairs (Extended Data Table 5). Consequently, some of the genotype calls for these samples may differ between the interim data release and this final data release (see below). Points represent participants, and coloured lines between points indicate their inferred relationship (for example, blue lines join full siblings). We acknowledge Wellcome Trust Core Awards 090532/Z/09/Z and 203141/Z/16/Z and grants 095552/Z/11/Z (to P.D. CAS  46, 1173–1186 (2014). These error rates are similar to those produced by other phasing methods that can handle data at this scale42,43. Google Scholar. Both papers drew on data from the … UK Biobank. The UK biobank resource with deep phenotyping and genomic data. and JavaScript. The UK Biobank resource with deep phenotyping and genomic data Clare Bycroft et al. We also imputed classical allelic variation at 11 human leukocyte antigen (HLA) genes, and replicated signals of known associations between HLA alleles and many common diseases. Summary of the major components of the UK Biobank resource. The symbols (shapes and colours) indicate the self-reported ethnic background of each participant. b, Distribution of the number of relatives that participants have in the UK Biobank cohort. For both the sex-specific region and the pseudo-autosomal regions (PAR), samples were excluded which were identified as having a likely sex chromosome aneuploidy (see above). Dilthey, A. et al. Axiom Genotyping Solution Data Analysis Guide http://tools.thermofisher.com/content/sfs/manuals/axiom_genotyping_solution_analysis_guide.pdf (2017). This dataset consisted of 16,175 autosomal markers. Fast principal-component analysis reveals convergent evolution of ADH1B in Europe and East Asia. We imputed HLA types at two-field (also known as four-digit) resolution for 11 classical HLA genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DPA1 and HLA-DPB1) using the HLA*IMP:02 algorithm with a multi-population reference panel (Supplementary Tables 5 and 6)30 and validated the accuracy using a cross-validation experiment. We found credible sets for standing height using the method described previously33 and summarize the results in Extended Data Fig. The number of 95% credible sets that contain just 1 marker is 123 in UK Biobank and 76 in GIANT. Reset filters Year. Routine quality checks were carried out during the process of sample retrieval, DNA extraction36, and genotype calling37. Many markers were included because of known associations with, or possible roles in, disease. It is hoped that this will lead to more successful drug development1, and potentially to more efficient and personalized treatments. The application of our quality control pipeline resulted in the released dataset of 488,377 samples and 805,426 markers from both arrays with the properties shown in Fig. Across the entire cohort, there were 106 batches of 4,700 UK Biobank samples each (Supplementary Information, Supplementary Table 12). Nat. J.M. We confirmed that the shared parent must be their father because they do not all carry the same mitochondrial alleles, and the males all have the same Y chromosome alleles (data not shown). The colours indicate the proportions of each relatedness class within a bar. Fuchsberger, C. et al. https://doi.org/10.1038/s41586-018-0579-z, DOI: https://doi.org/10.1038/s41586-018-0579-z, Frontiers in Pharmacology d, Mean log2 ratios (L2R) on X and Y chromosomes for each sample, indicating probable sex chromosome aneuploidy (see Methods). For the larger prior, the number of single-marker credible sets was unaffected except for analysis B in UK Biobank (from 123 to 122), and the median proportion of markers in the credible set was unaffected in all analyses. The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, … 31) for HLA alleles and each disease using logistic regression. Following this, 438,427 participants were genotyped using the closely related Applied Biosystems UK Biobank Axiom Array (825,927 markers) that shares 95% of marker content with the UK BiLEVE Axiom Array. See Affymetrix Axiom Genotyping Solution Data Analysis Guide16 for more details of Affymetrix genotype calling. The exact number of samples with genetic data currently available in UK Biobank may differ slightly from those described in this paper. 6, 8111 (2015). For markers that failed at least one test in a given batch, we set the genotype calls in that batch to missing. b, Association statistics (from linear mixed model, see Methods) for UK Biobank markers in the genotype data (n = 343,321). They also provided blood, urine and saliva samples, which were stored in such a way as to allow many different types of assay to be performed (for example, genetic, proteomic and metabonomic analyses)7. Haplotype estimation for biobank-scale datasets. A multi-modal imaging assessment is currently underway, which comprises magnetic resonance imaging (MRI) of the brain9, heart10 and body, carotid ultrasound11 and a whole body dual-energy X-ray absorptiometry of the bones and joints12. The larger than expected number of related pairs could be explained by sampling bias due to, for example, an individual being more likely to agree to participate because a family member was also involved. The UK Biobank genetic data contains genotypes for 488,377 participants. The open resource is unique in its size and scope. For almost all samples (99.9%), the self-reported and the inferred sex are the same, but for a small number of samples (378) they do not match (see Supplementary Information for discussion). Using this new format, the full imputed files require 2.1 Tb of file space. and P.D. Genetics, Search Publications: Search. Genet. We then confirmed that the effect size estimates for overlapping markers were comparable between the two studies. By considering the relationship types and the age and sex of the individuals within each family group, we identified 1,066 sets of trios (two parents and an offspring), which comprise 1,029 unique sets of parents and 37 quartets (two parents and two children). Ethics approval for the UK Biobank study was obtained from the North West Centre for Research Ethics Committee (11/NW/0382). We did not remove samples from the data as a result of any of the above analyses, but rather provide the information as part of the data release. Extended Data Fig. A red solid line on a plot indicates where x = y. a, Both plots compare the number of markers in the 95% credible sets in which the size is less than 18 markers in both studies (363 regions in the left-hand plot; 445 in the right-hand plot). CAS PubMed PubMed Central Google Scholar 11. Lek, M. et al. Huang, J. et al. For example, the first two principal components separate out individuals with sub-Saharan African ancestry, European ancestry and east Asian ancestry. Genet. and GWAS testing (C.B., C.F. By submitting a comment you agree to abide by our Terms and Community Guidelines. The remaining panels show distributions in tranches of MAF; MAF > 5%, 1% ≤ MAF < 5%, 0.1% ≤ MAF < 1%, 0.01% ≤ MAF < 0.1% and 0.001% ≤ MAF < 0.01%. All participants provided consent for follow-up through linkage to their health-related records. Nat. For example, the number of sibling pairs (22,666) is roughly twice as many as would theoretically be expected in a random sample (of this size) of the eligible UK population, after taking into account typical family sizes (Supplementary Table 4). Percentages in brackets are the proportion of the union of such windows across all three data sources (1,215). The ellipses indicate the location and shape of the posterior probability distribution (two-dimensional multivariate normal) of the transformed intensities for the three genotypes in the stated batch. For the PAR, we additionally excluded samples with a missing rate of >5% among markers in the PAR. Close relationships (for example, siblings) among UK Biobank participants were not recorded during the collection of other phenotypic information. The colours indicate different combinations of self-reported sex, and sex inferred by Affymetrix (from the genetic data). Special attention was paid in the automated sample retrieval process at UK Biobank to ensure that experimental units such as plates or timing of extraction did not correlate systematically with baseline phenotypes such as age, sex, and ethnic background, or the time and location of sample collection. The UK Biobank. 2a–c. e, Comparison of Z-scores in UK Biobank (y axis) and GIANT (x axis). The International Multiple Sclerosis Genetics Consortium. Manichaikul, A. et al. Affymetrix. https://github.com/wtsi-medical-genomics/evoker, http://hgdownload.cse.ucsc.edu/goldenpath/hg19/database/, http://www.well.ox.ac.uk/~gav/bgen_format/bgen_format.html, https://bitbucket.org/wkretzsch/hapfuse/src, http://www.ukbiobank.ac.uk/register-apply/, http://www.ukbiobank.ac.uk/scientists-3/genetic-data/, http://biobank.ctsu.ox.ac.uk/crystal/label.cgi?id=100314, http://www.ukbiobank.ac.uk/wp-content/uploads/2014/04/UK-Biobank-Axiom-Array-Content-Summary-2014.pdf, http://biobank.ctsu.ox.ac.uk/crystal/docs/genotyping_qc.pdf, https://biobank.ctsu.ox.ac.uk/crystal/docs/TouchscreenQuestionsMainFinal.pdf, http://tools.thermofisher.com/content/sfs/manuals/axiom_genotyping_solution_analysis_guide.pdf, http://www.ukbiobank.ac.uk/wp-content/uploads/2011/11/UK-Biobank-Protocol.pdf, http://biobank.ndph.ox.ac.uk/showcase/docs/affy_data_generation2017.pdf, https://biobank.ctsu.ox.ac.uk/crystal/docs/genotyping_sample_workflow.pdf, http://biobank.ndph.ox.ac.uk/showcase/docs/affy_lab_process2017.pdf. Genet. Multi-trait Genome-Wide Analyses of the Brain Imaging Phenotypes in UK Biobank. The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. Article  J. 1. are founders and directors of Genomics Plc. 4d, e and the credible set analysis we used autosomal markers only, and filtered markers in each data source such that MAF > 0.001 (defined in the GWAS population), and Info score > 0.3 in the UK Biobank imputed data. Nat. The UK Biobank is a powerful example of the immense value that can be achieved from large population scale studies that combine genetics with extensive and deep phenotyping and linkage to health records coupled with a strong data sharing policy. 115, 681–686 (2016). To assess the effectiveness of UK Biobank genomic data for fine-mapping within associated loci, we computed 95% credible sets33 for 575 regions that contain at least one genome-wide significant marker (P < 5 × 10−8) in both GIANT and the UK Biobank imputed data (see Methods). In this paper, we summarize the existing and planned content of the phenotype resource and describe the genetic dataset on the full 500,000 participants. For example, we adjusted heterozygosity for population structure by fitting a linear regression model with the first six principal components in a PCA as predictors (Extended Data Fig. Loh, P.-R., Palamara, P. F. & Price, A. L. Fast and accurate long-range phasing in a UK Biobank cohort. News & Views, Nature The confounding effect of cryptic relatedness for environmental risks of systolic blood pressure on cohort studies. The integers show the total number of family networks in the cohort (if more than one) with that same configuration, ignoring third-degree pairs. The black dotted line shows x = y, and the red solid line shows the linear regression line estimated on these data. A more detailed description of the array content is available in the UK Biobank Axiom Array Content Summary2. Genet. For Fig. A list of these samples is provided as part of the data release. and J.M. Extreme values in one or both of these metrics can be indicators of poor sample quality due to, for example, DNA contamination15. The UK Biobank is a prospective cohort study that recruited over 500,000 middle-aged individuals between the years 2006 and 2010, allowing for linkage of extensive baseline, genetic and clinical data [ 3 ]. Full documentation about the genetic data released by UK Biobank has been detailed in this publication: Bycroft et al.
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