Exome sequencing and characterization of 49,960 individuals in the UK Biobank

Abstract

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Fine-mapping and cell-specific enrichment at corneal resistance factor loci prioritize candidate causal regulatory variants

“…It is a component of the ECM in muscle, vessels and skin—tissues which display the most prominent features of type VI collagenopathies. Recent exome sequence analysis in UKBB 46 reported significant large effects on CRF of a burden of rare loss of function coding variants in COL6A1; rs8127032 could shed light on cis-regulatory control of this gene. Drawing on the ever-increasing regulatory annotations of the genome, particularly on experimentally defined trans-acting factors binding sites, could further shape precise hypotheses to be tested.…”

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

“…We compared the correlation of genotypes between the exome-sequencing data released by the UK Biobank (following their SPB pipeline 113 ) and the TOPMed-imputed genotypes. The comparison assessed 49,819 individuals and 3,052,260 autosomal variants that were found in both the exome-sequencing and TOPMed-imputed datasets (matched by chromosome, position and alleles, and with an imputation quality of at least 0.3 in the TOPMed-imputed data).…”

Open-source mapping and variant calling for large-scale NGS data from original base-quality scores

“…Variants were called on each CRAM with DeepVariant 5 0.10.0 using a deep learning model retrained on exome data sequenced with the same protocol as was used to sequence the UK Biobank samples 8 . Variant calls were restricted to the exome capture region and the 100 base-pairs flanking each capture target, resulting in a gVCF (genomic VCF) for each sample containing all variant genotypes and compressed representations of reference regions without called variant genotypes.…”

“…Two sets of NovaSeq exome sequence data were generated from the HG002 control sample 10 via the exome sequencing protocol applied to UK Biobank samples 8 and then mapped via the OQFE protocol. Two additional CRAMs were created from each HG002 OQFE CRAM by recalibrating the base qualities (+BQSR CRAM) and then applying the FE binning strategy (+BQSR+FEbin CRAM) as described in the FE protocol 4 .…”