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

Author:

Stefanucci Luca123ORCID,Collins Janine124ORCID,Sims Matthew C.1256ORCID,Barrio-Hernandez Inigo7ORCID,Sun Luanluan8,Burren Oliver S.9ORCID,Perfetto Livia710ORCID,Bender Isobel11ORCID,Callahan Tiffany J.12ORCID,Fleming Kathryn13,Guerrero Jose A.24ORCID,Hermjakob Henning7ORCID,Martin Maria J.7ORCID,Stephenson James7ORCID,Paneerselvam Kalpana7ORCID,Petrovski Slavé1415ORCID,Porras Pablo7ORCID,Robinson Peter N.1617ORCID,Wang Quanli9,Watkins Xavier7,Frontini Mattia12318ORCID,Laskowski Roman A.7ORCID,Beltrao Pedro19ORCID,Di Angelantonio Emanuele3820212223,Gomez Keith24ORCID,Laffan Mike2526ORCID,Ouwehand Willem H.1227ORCID,Mumford Andrew D.13ORCID,Freson Kathleen28,Carss Keren9ORCID,Downes Kate1229,Gleadall Nick12ORCID,Megy Karyn1,Bruford Elspeth17ORCID,Vuckovic Dragana30ORCID

Affiliation:

1. 1Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom

2. 2National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom

3. 3British Heart Foundation, BHF Centre of Research Excellence, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom

4. 4Department of Haematology, Barts Health NHS Trust, London, United Kingdom

5. 5Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, United Kingdom

6. 6Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom

7. 7European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom

8. 8Department of Public Health and Primary Care, BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom

9. 9Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom

10. 10Department of Biology and Biotechnology “C.Darwin,” Sapienza University of Rome, Rome, Italy

11. 11Department of Biochemistry, University of Oxford, Oxford, United Kingdom

12. 12Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY

13. 13School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom

14. 14Centre for Genomics Research, Discovery Sciences, AstraZeneca, Cambridge, United Kingdom

15. 15Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Australia

16. 16Genomic Medicine, The Jackson Laboratory, Farmington, CT

17. 17Institute for Systems Genomics, University of Connecticut, Farmington, CT

18. 18Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences RILD Building, University of Exeter Medical School, Exeter, United Kingdom

19. 19Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland

20. 20Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom

21. 21NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, United Kingdom

22. 22Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom

23. 23Health Data Science Centre, Human Technopole, Milan, Italy

24. 24Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom

25. 25Department of Haematology, Imperial College Healthcare NHS Trust, London, United Kingdom

26. 26Department of Immunology and Inflammation, Centre for Haematology, Imperial College London, London, United Kingdom

27. 27Department of Haematology, University College London Hospitals NHS Trust, London, United Kingdom

28. 28Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KULeuven, Leuven, Belgium

29. 29Cambridge Genomics Laboratory, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom

30. 30Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3