William J. Astle

National Health Service

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Co-Authors

Willem H. Ouwehand

NHS Blood and Transplant

Ernest Turro

Icahn School of Medicine at Mount Sinai

Mattia Frontini

National Health Service

Karyn Mégy

AstraZeneca (United Kingdom)

Adam S. Butterworth

University of Cambridge

Sylvia Richardson

MRC Biostatistics Unit

Kate Downes

University of Cambridge

Andrew Mumford

University of Bristol

Stuart Meacham

European Bioinformatics Institute

Taco W. Kuijpers

University of Amsterdam

Cooperative Institutions

University of Cambridge

551

University College London

385

National Institute for Health Research

262

National Health Service

244

Wellcome Sanger Institute

199

University of Oxford

196

Cambridge University Hospitals NHS Foundation Trust

195

Addenbrooke's Hospital

187

Medical Research Council

164

Imperial College London

160

Author Statistics

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Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Nature Communications (2019)

Paul Lyons James E. Peters Federico Alberici James Liley Richard Coulson

Abstract Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Granulomatosis with polyangiitis

Genome-wide Association Study

10.1038/s41467-019-12515-9

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Citations (206)

The Polygenic and Monogenic Basis of Blood Traits and Diseases

medRxiv (Cold Spring Harbor Laboratory) (2020)

Dragana Vuckovic Erik L. Bao Parsa Akbari Caleb A. Lareau Abdou Mousas

Summary Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.

Genome-wide Association Study

Genetic architecture

Mendelian inheritance

Human genetic variation

Genetic Association

Human genetics

Polygene

Blood cell

10.1101/2020.02.02.20020065

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Citations (4)

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Blood (2020)

Matthew C. Sims Louisa Mayer Janine Collins Tadbir K. Bariana Karyn Mégy

Immune Dysregulation

10.1182/blood.2019004776

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Citations (42)

A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology

Nature Communications (2023)

Parsa Akbari Dragana Vuckovic Luca Stefanucci Tao Jiang Kousik Kundu

Abstract Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes—including cell-type specific measures of granularity, nucleic acid content and reactivity—in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types—variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.

Genome-wide Association Study

Cell type

Genetic Association

10.1038/s41467-023-40679-y

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Citations (11)

Whole-genome sequencing of patients with rare diseases in a national health system

Nature (2020)

Ernest Turro William J. Astle Karyn Mégy Stefan Gräf Daniel Greene

10.1038/s41586-020-2434-2

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Citations (443)

Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

Journal of Clinical Investigation (2017)

Irina Pleines Joanne Woods Stéphane Chappaz Verity G. Kew Nicola Foad

Platelets are anuclear cells that are essential for blood clotting. They are produced by large polyploid precursor cells called megakaryocytes. Previous genome-wide association studies in nearly 70,000 individuals indicated that single nucleotide variants (SNVs) in the gene encoding the actin cytoskeletal regulator tropomyosin 4 (TPM4) exert an effect on the count and volume of platelets. Platelet number and volume are independent risk factors for heart attack and stroke. Here, we have identified 2 unrelated families in the BRIDGE Bleeding and Platelet Disorders (BPD) collection who carry a TPM4 variant that causes truncation of the TPM4 protein and segregates with macrothrombocytopenia, a disorder characterized by low platelet count. N-Ethyl-N-nitrosourea–induced (ENU-induced) missense mutations in Tpm4 or targeted inactivation of the Tpm4 locus led to gene dosage–dependent macrothrombocytopenia in mice. All other blood cell counts in Tpm4-deficient mice were normal. Insufficient TPM4 expression in human and mouse megakaryocytes resulted in a defect in the terminal stages of platelet production and had a mild effect on platelet function. Together, our findings demonstrate a nonredundant role for TPM4 in platelet biogenesis in humans and mice and reveal that truncating variants in TPM4 cause a previously undescribed dominant Mendelian platelet disorder.

Platelet disorder

Mean platelet volume

Tropomyosin

10.1172/jci86154

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Citations (64)

SNP in human ARHGEF3 promoter is associated with DNase hypersensitivity, transcript level and platelet function, and Arhgef3 KO mice have increased mean platelet volume

PLoS ONE (2017)

Siying Zou Alexandra M. Teixeira Myrto Kostadima William J. Astle Aparna Radhakrishnan

Genome-wide association studies have identified a genetic variant at 3p14.3 (SNP rs1354034) that strongly associates with platelet number and mean platelet volume in humans. While originally proposed to be intronic, analysis of mRNA expression in primary human hematopoietic subpopulations reveals that this SNP is located directly upstream of the predominantly expressed ARHGEF3 isoform in megakaryocytes (MK). We found that ARHGEF3, which encodes a Rho guanine exchange factor, is dramatically upregulated during both human and murine MK maturation. We show that the SNP (rs1354034) is located in a DNase I hypersensitive region in human MKs and is an expression quantitative locus (eQTL) associated with ARHGEF3 expression level in human platelets, suggesting that it may be the causal SNP that accounts for the variations observed in human platelet traits and ARHGEF3 expression. In vitro human platelet activation assays revealed that rs1354034 is highly correlated with human platelet activation by ADP. In order to test whether ARHGEF3 plays a role in MK development and/or platelet function, we developed an Arhgef3 KO/LacZ reporter mouse model. Reflecting changes in gene expression, LacZ expression increases during MK maturation in these mice. Although Arhgef3 KO mice have significantly larger platelets, loss of Arhgef3 does not affect baseline MK or platelets nor does it affect platelet function or platelet recovery in response to antibody-mediated platelet depletion compared to littermate controls. In summary, our data suggest that modulation of ARHGEF3 gene expression in humans with a promoter-localized SNP plays a role in human MKs and human platelet function—a finding resulting from the biological follow-up of human genetic studies. Arhgef3 KO mice partially recapitulate the human phenotype.

Mean platelet volume

10.1371/journal.pone.0178095

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Citations (24)

SMIM1 absence is associated with reduced energy expenditure and excess weight

Med (2024)

Luca Stefanucci Camous Moslemi Ana R. Tomé Sam Virtue Guillaume Bidault

Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.

10.1016/j.medj.2024.05.015

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Citations (0)

Bayesian Inference Associates Rare KDR Variants With Specific Phenotypes in Pulmonary Arterial Hypertension

Circulation Genomic and Precision Medicine (2020)

Emilia M. Swietlik Daniel Greene Na Zhu Karyn Mégy Marcella Cogliano

Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Genome-wide Association Study

10.1161/circgen.120.003155

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Citations (38)

Inhibition of MRP1 Induces Fetal Hemoglobin through NRF2 Activation to Protect Human Erythroid Cells from Sickling

Blood (2022)

Yannis Hara Emily Kawabata Viktor T. Lemgart Paola G. Bronson Alexandra Hicks

10.1182/blood-2022-168169

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Citations (0)