دورية أكاديمية
أعرض في EDS

The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants.

التفاصيل البيبلوغرافية
العنوان: The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants.
المؤلفون: Stefanucci L; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.; British Heart Foundation, BHF Centre of Research Excellence, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom., Collins J; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Department of Haematology, Barts Health NHS Trust, London, United Kingdom., Sims MC; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, United Kingdom.; Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom., Barrio-Hernandez I; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Sun L; Department of Public Health and Primary Care, BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom., Burren OS; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Perfetto L; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom.; Department of Biology and Biotechnology 'C.Darwin,' Sapienza University of Rome, Rome, Italy., Bender I; Department of Biochemistry, University of Oxford, Oxford, United Kingdom., Callahan TJ; Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY., Fleming K; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom., Guerrero JA; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Department of Haematology, Barts Health NHS Trust, London, United Kingdom., Hermjakob H; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Martin MJ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Stephenson J; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Paneerselvam K; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Petrovski S; Centre for Genomics Research, Discovery Sciences, AstraZeneca, Cambridge, United Kingdom.; Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Australia., Porras P; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Robinson PN; Genomic Medicine, The Jackson Laboratory, Farmington, CT.; Institute for Systems Genomics, University of Connecticut, Farmington, CT., Wang Q; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Watkins X; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Frontini M; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.; British Heart Foundation, BHF Centre of Research Excellence, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences RILD Building, University of Exeter Medical School, Exeter, United Kingdom., Laskowski RA; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Beltrao P; Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland., Di Angelantonio E; British Heart Foundation, BHF Centre of Research Excellence, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Department of Public Health and Primary Care, BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.; Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom.; NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, United Kingdom.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom.; Health Data Science Centre, Human Technopole, Milan, Italy., Gomez K; Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom., Laffan M; Department of Haematology, Imperial College Healthcare NHS Trust, London, United Kingdom.; Department of Immunology and Inflammation, Centre for Haematology, Imperial College London, London, United Kingdom., Ouwehand WH; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Department of Haematology, University College London Hospitals NHS Trust, London, United Kingdom., Mumford AD; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom., Freson K; Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KULeuven, Leuven, Belgium., Carss K; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Downes K; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Cambridge Genomics Laboratory, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom., Gleadall N; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom., Megy K; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom., Bruford E; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom., Vuckovic D; Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.
المصدر: Blood [Blood] 2023 Dec 14; Vol. 142 (24), pp. 2055-2068.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
أسماء مطبوعة: Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]
مواضيع طبية MeSH: Genome-Wide Association Study* , Thrombosis*, Humans ; Biological Specimen Banks ; Hemostasis ; Hemorrhage/genetics ; Rare Diseases
مستخلص: Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each independent variant and improve their pathogenicity classification. Our study of 140 214 unrelated UK Biobank (UKB) participants found that each of them carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade gene (DGG) variants for rare bleeding, thrombotic, and platelet disorders (BTPDs) observed in 12 367 UKB participants. By association analysis, for a subset of these variants, we estimated effect sizes for platelet count and volume, and odds ratios for bleeding and thrombosis. Variants causal of some autosomal recessive platelet disorders revealed phenotypic consequences in carriers. Loss-of-function variants in MPL, which cause chronic amegakaryocytic thrombocytopenia if biallelic, were unexpectedly associated with increased platelet counts in carriers. We also demonstrated that common variants identified by genome-wide association studies (GWAS) for platelet count or thrombosis risk may influence the penetrance of rare variants in BTPD DGGs on their associated hemostasis disorders. Network-propagation analysis applied to an interactome of 18 410 nodes and 571 917 edges showed that GWAS variants with large effect sizes are enriched in DGGs and their first-order interactors. Finally, we illustrate the modifying effect of polygenic scores for platelet count and thrombosis risk on disease severity in participants carrying rare variants in TUBB1 or PROC and PROS1, respectively. Our findings demonstrate the power of association analyses using large population datasets in improving pathogenicity classifications of rare variants.
(© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
التعليقات: Comment in: Blood. 2023 Dec 14;142(24):2037-2038. (PMID: 38095926)
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معلومات مُعتمدة: T15 LM007079 United States LM NLM NIH HHS; T15 LM009451 United States LM NLM NIH HHS; MR/P02002X/1 United Kingdom MRC_ Medical Research Council; MR/R002363/1 United Kingdom MRC_ Medical Research Council; U24 HG003345 United States HG NHGRI NIH HHS; United Kingdom WT_ Wellcome Trust
تواريخ الأحداث: Date Created: 20230830 Date Completed: 20231216 Latest Revision: 20240324
رمز التحديث: 20240324
مُعرف محوري في PubMed: PMC10733830
DOI: 10.1182/blood.2023020118
PMID: 37647632
قاعدة البيانات: MEDLINE
الوصف
تدمد:1528-0020
DOI:10.1182/blood.2023020118