The Polygenic and Monogenic Basis of Blood Traits and Diseases.

UK Biobank; blood; chromatin; fine-mapping; genetics; hematopoiesis; omnigenic; polygenic risk; rare disease; splicing; Female; Gene Regulatory Networks/genetics; Genetic Predisposition to Disease/genetics; Genome-Wide Association Study/methods; Hematopoiesis/genetics; Humans; Male; Multifactorial Inheritance/genetics; Phenotype; Polymorphism, Single Nucleotide/genetics; Gene Regulatory Networks; Genetic Predisposition to Disease; Genome-Wide Association Study; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology

Abstract :

[en] Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range 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 traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Disciplines :

Genetics & genetic processes

Author, co-author :

Vuckovic, Dragana; Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK, National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK

Bao, Erik L; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA, Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, 02142, USA

Akbari, Parsa; Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK, National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK, MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK, Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK

Lareau, Caleb A; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA

Mousas, Abdou; Montreal Heart Institute, Montreal, Quebec, H1T 1C8, Canada

Jiang, Tao; Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, UK, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK

Chen, Ming-Huei; The Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, 01702, USA, Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, 01702, USA

Raffield, Laura M; Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA

Tardaguila, Manuel; Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK

Huffman, Jennifer E; Center for Population Genomics, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, 02130, USA

More authors (103 more)

Language :

English

Title :

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Publication date :

03 September 2020

Journal title :

Cell

ISSN :

0092-8674

eISSN :

1097-4172

Publisher :

Cell Press, United States

Volume :

182

Issue :

Pages :

1214 - 1231.e11

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://api.elsevier.com/content/article/PII:S0092867420309995?httpAccept=text/xml

Funders :

NIHR - National Institute for Health Research [GB]
NIH - National Institutes of Health [US-MD] [US-MD]
Wellcome Trust [GB]

Funding text :

We thank all participants. This research has been conducted using the UK Biobank Resource under Application Number 13745. A full list of acknowledgments appears in the Extended Acknowledgments and Author Contributions ( Document S1). Writing – Original Draft, D.V. E.L.B. P.A. C.A.L. N.S. V.G.S. P.A. W.J.A. P.L.A. A.S.B. A.P.R. A.D.J. G.L. and W.H.O.; Writing – Review & Editing, All authors contributed and discussed the results and commented on the manuscript; Data curation, methodology, software and formal analysis group, D.V. E.L.B. P.A. C.A.L. T.J. S.C.R. A.M. M.-H.C. L.M.R. J.E.H. Q.G. E.M.W. M.T. K.M. C.J.P. H.P. P.S. and P.K.A.; Conceptualization and supervision, N.S. V.G.S. G.L. W.H.O. A.S.B. A.P.R. W.J.A. P.L.A. A.D.J. M.I. D.J.R. E.D.A. and J.D. A full list of contributions appears in the Extended Acknowledgments and Author Contributions ( Document S1). Adam Butterworth has received grants (outside of this work) from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, and Sanofi; James Floyd has consulted for Shionogi; Qi Guo is a full-time employee of BenevolentAI; Joanna Howson is a full-time employee of Novo Nordisk. Parsa Akbari is a full-time employee of Regeneron Pharmaceuticals.

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