The UK10K project identifies rare variants in health and disease.
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ABSTRACT:
SUBMITTER: UK10K Consortium
PROVIDER: S-EPMC4773891 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.
| S-EPMC4579394 | biostudies-literature
Project description:UnlabelledHigh-throughput sequencing technologies survey genetic variation at genome scale and are increasingly used to study the contribution of rare and low-frequency genetic variants to human traits. As part of the Cohorts arm of the UK10K project, genetic variants called from low-read depth (average 7×) whole genome sequencing of 3621 cohort individuals were analysed for statistical associations with 64 different phenotypic traits of biomedical importance. Here, we describe a novel genome browser based on the Biodalliance platform developed to provide interactive access to the association results of the project.Availability and implementationThe browser is available at http://www.uk10k.org/dalliance.html. Source code for the Biodalliance platform is available under a BSD license from http://github.com/dasmoth/dalliance, and for the LD-display plugin and backend from http://github.com/dasmoth/ldserv.
| S-EPMC4673976 | biostudies-literature
Project description:Deep vein thrombosis and pulmonary embolism, collectively defined as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Common genetic variants conferring increased varying degrees of VTE risk have been identified by genome-wide association studies (GWAS). Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 result in perinatal lethal thrombosis in homozygotes and markedly increased VTE risk in heterozygotes. However, currently described VTE variants account for an insufficient portion of risk to be routinely used for clinical decision making. To identify new rare VTE risk variants, we performed a whole-exome study of 393 individuals with unprovoked VTE and 6114 controls. This study identified 4 genes harboring an excess number of rare damaging variants in patients with VTE: PROS1, STAB2, PROC, and SERPINC1. At STAB2, 7.8% of VTE cases and 2.4% of controls had a qualifying rare variant. In cell culture, VTE-associated variants of STAB2 had a reduced surface expression compared with reference STAB2. Common variants in STAB2 have been previously associated with plasma von Willebrand factor and coagulation factor VIII levels in GWAS, suggesting that haploinsufficiency of stabilin-2 may increase VTE risk through elevated levels of these procoagulants. In an independent cohort, we found higher von Willebrand factor levels and equivalent propeptide levels in individuals with rare STAB2 variants compared with controls. Taken together, this study demonstrates the utility of gene-based collapsing analyses to identify loci harboring an excess of rare variants with functional connections to a complex thrombotic disease.
| S-EPMC7393257 | biostudies-literature
Project description:Copy-number variants (CNVs) are substantial contributors to human disease. A central challenge in CNV-disease association studies is to characterize the pathogenicity of rare and possibly incompletely penetrant events, which requires the accurate detection of rare CNVs in large numbers of individuals. Cost and throughput issues limit our ability to perform these studies. We have adapted the Illumina BeadXpress SNP genotyping assay and developed an algorithm, SNP-Conditional OUTlier detection (SCOUT), to rapidly and accurately detect both rare and common CNVs in large cohorts. This approach is customizable, cost effective, highly parallelized, and largely automated. We applied this method to screen 69 loci in 1105 children with unexplained intellectual disability, identifying pathogenic variants in 3.1% of these individuals and potentially pathogenic variants in an additional 2.3%. We identified seven individuals (0.7%) with a deletion of 16p11.2, which has been previously associated with autism. Our results widen the phenotypic spectrum of these deletions to include intellectual disability without autism. We also detected 1.65-3.4 Mbp duplications at 16p13.11 in 1.1% of affected individuals and 350 kbp deletions at 15q11.2, near the Prader-Willi/Angelman syndrome critical region, in 0.8% of affected individuals. Compared to published CNVs in controls they are significantly (P = 4.7 x 10(-5) and 0.003, respectively) enriched in these children, supporting previously published hypotheses that they are neurocognitive disease risk factors. More generally, this approach offers a previously unavailable balance between customization, cost, and throughput for analysis of CNVs and should prove valuable for targeted CNV detection in both research and diagnostic settings.
| S-EPMC2752120 | biostudies-literature
Project description:More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ? 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.
| S-EPMC3378381 | biostudies-literature
Project description:Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.
| S-EPMC9700438 | biostudies-literature
Project description:Atrioventricular septal defect (AVSD) is a deleterious subtype of congenital heart diseases (CHD) characterized by atrioventricular canal defect. The pathogenic genetic changes of AVSD remain elusive, particularly for copy number variation (CNV), a large segment variation of the genome, which is one of the major forms of genetic variants resulting in congenital heart diseases. In the present study, we recruited 150 AVSD cases and 100 healthy subjects as controls for whole exome sequencing (WES). We identified total 4255 rare CNVs using exon Hidden Markov model (XHMM) and screened rare CNVs by eliminating common CNVs based on controls and Database of Genomic Variants (DGV). Each patient contained at least 9 CNVs, and the CNV burden was prominently presented in chromosomes 19,22,21&16. Small CNVs (<500 kb) were frequently observed. By leveraging gene-based burden test, we further identified 20 candidate AVSD-risk genes. Among them, DYRK1A, OBSCN and TTN were presented in the core disease network of CHD and highly and dynamically expressed in the heart during the development, which indicated they possessed the high potency to be AVSD-susceptible genes. These findings not only provided a roadmap for finally unveiling the genetic cause of AVSD, but also provided more resources and proofs for clinical genetics.
| S-EPMC9936062 | biostudies-literature
Project description:BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.
| S-EPMC3686259 | biostudies-other
Project description:BackgroundIn European Union countries, any disease affecting less than 5 people in 10,000 is considered rare. As expertise is scarce and rare diseases (RD) are complex, RD patients can remain undiagnosed for many years. The period of searching for a diagnosis, called diagnostic delay, sometimes leads to a diagnostic dead end when the patient's disease is impossible to diagnose after undergoing all available investigations. In recent years, extensive efforts have been made to support the implementation of ORPHA nomenclature in health information systems (HIS) so as to allow RD coding. Until recently, the nomenclature only encompassed codes for specific RD. Persons suffering from a suspected RD who could not be diagnosed even after full investigation, could not be coded with ORPHAcodes. The recognition of the RD status is necessary for patients, even if they do not have a precise diagnosis. It can facilitate reimbursement of care, be socially and psychologically empowering, and grant them access to scientific advances.ResultsThe RD-CODE project aimed at making those patients identifiable in HIS in order to produce crucial epidemiological data. Undiagnosed patients were defined as patients for whom no clinically-known disorder could be confirmed by an expert center after all reasonable efforts to obtain a diagnosis according to the state-of-the-art and diagnostic capabilities available. Three recommendations for the coding of undiagnosed RD patients were produced by a multi-stakeholder panel of experts: 1/ Capture the diagnostic ascertainment for all rare disease cases; 2/ Use the newly created ORPHAcode (ORPHA:616874 "Rare disorder without a determined diagnosis after full investigation"), available in the Orphanet nomenclature: as the code is new, guidelines are essential to ensure its correct and homogeneous use for undiagnosed patients' identification in Europe and beyond; 3/ Use additional descriptors in registries.ConclusionsThe recommendations can now be implemented in HIS (electronic health records and/or registries) and could be a game-changer for patients, clinicians and researchers in the field, enabling assessment of the RD population, including undiagnosed patients, adaptation of policy measures including financing for care and research programs, and to improved access of undiagnosed patients to research programs.
| S-EPMC10822150 | biostudies-literature
Project description:The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10-6), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.
| S-EPMC8775355 | biostudies-literature