The sequences of 150,119 genomes in the UK Biobank

Nature, Journal Year: 2022, Volume and Issue: 607(7920), P. 732 - 740

Published: July 20, 2022

Detailed knowledge of how diversity in the sequence human genome affects phenotypic depends on a comprehensive and reliable characterization both sequences variation. Over past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome large cohorts with rich data1,2. Here we describe analysis 150,119 individuals UK Biobank3. This constitutes set high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% all possible 58,707,036 indels. variants allows us to characterize selection based variation within population through depletion rank score windows along genome. Depletion shows that coding exons represent small fraction regions subject strong conservation. We define three Biobank: British Irish cohort, smaller African cohort South Asian cohort. A haplotype reference panel is provided imputation most carried by more sequenced individuals. identified 895,055 structural 2,536,688 microsatellites, groups typically excluded large-scale studies. Using formidable new resource, provide several examples trait associations for rare effects not found previously studies and/or imputation.

Language: Английский

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The next-generation Open Targets Platform: reimagined, redesigned, rebuilt

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 51(D1), P. D1353 - D1359

Published: Nov. 18, 2022

The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, rebuilt the in order streamline data integration harmonisation, expand ways which users can explore data, improve user experience. gene-disease causal evidence has been enhanced expanded better capture disease causality across rare, common, somatic diseases. For annotations, incorporated new features that help assess safety tractability, including genetic constraint, PROTACtability assessments, AlphaFold structure predictions. We also introduced machine learning applications for knowledge extraction from published literature, clinical trial information, labels. technologies frameworks since update will ease introduction of creation separate instances adapted requirements. Our Community forum, training materials, outreach programme support a range use cases.

Language: Английский

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Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(8), P. 1155 - 1166

Published: July 14, 2022

Abstract Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over third people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map landscape inherited predisposition CH, increasing number germline associations with CH in European-ancestry populations 4 14. Genes at new loci implicate DNA damage repair ( PARP1 , ATM CHEK2 ), hematopoietic migration/homing CD164 ) myeloid oncogenesis SETBP1 ). Several were CH-subtype-specific including variants TCL1A that had opposite DNMT3A - versus TET2 -mutant two most common subtypes, proposing key roles for these development. Mendelian randomization analyses showed smoking longer leukocyte telomere length are causal risk factors increases risks myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation epigenetic ageing.

Language: Английский

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Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes

Cell Genomics, Journal Year: 2022, Volume and Issue: 2(9), P. 100168 - 100168

Published: Aug. 15, 2022

Language: Английский

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Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(3), P. 240 - 250

Published: Feb. 17, 2022

Language: Английский

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Targeting the CCL2–CCR2 axis for atheroprotection

European Heart Journal, Journal Year: 2022, Volume and Issue: 43(19), P. 1799 - 1808

Published: Feb. 16, 2022

Decades of research have established atherosclerosis as an inflammatory disease. Only recently though, clinical trials provided proof-of-concept evidence for the efficacy anti-inflammatory strategies with respect to cardiovascular events, thus offering a new paradigm lowering residual vascular risk. Efforts target inflammasome-interleukin-1β-interleukin-6 pathway been highly successful, but inter-individual variations in drug response, lack reduction all-cause mortality, and higher rate infections also highlight need second generation agents targeting atherosclerosis-specific immune mechanisms while minimizing systemic side effects. CC-motif chemokine ligand 2/monocyte-chemoattractant protein-1 (CCL2/MCP-1) orchestrates monocyte trafficking between bone marrow, circulation, atherosclerotic plaques by binding its cognate receptor CCR2. Adding strong body data from experimental models, coherent series recent large-scale genetic observational epidemiological studies along human relevance therapeutic potential CCL2-CCR2 axis atherosclerosis. Here, we summarize pinpointing emerging Furthermore, contextualize previous efforts interfere this pathway, scrutinize approaches vs. targeting, discuss possible pathway-intrinsic opportunities challenges related pharmacological

Language: Английский

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Genetic associations of protein-coding variants in human disease

Nature, Journal Year: 2022, Volume and Issue: 603(7899), P. 95 - 102

Published: Feb. 23, 2022

Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk human disease. However, GWAS so far remained largely underpowered in relation identifying associations rare and low-frequency allelic spectrum lacked resolution trace causal mechanisms underlying genes

Language: Английский

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Polygenic architecture of rare coding variation across 394,783 exomes

Nature, Journal Year: 2023, Volume and Issue: 614(7948), P. 492 - 499

Published: Feb. 8, 2023

Language: Английский

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Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

The American Journal of Human Genetics, Journal Year: 2021, Volume and Issue: 109(1), P. 136 - 156

Published: Dec. 9, 2021

Language: Английский

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Using genetic association data to guide drug discovery and development: Review of methods and applications

The American Journal of Human Genetics, Journal Year: 2023, Volume and Issue: 110(2), P. 195 - 214

Published: Feb. 1, 2023

Language: Английский

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