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. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.
Bibliographical noteFunding Information:
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.
© 2020 The Authors
Copyright 2021 Elsevier B.V., All rights reserved.
- UK Biobank
- polygenic risk
- rare disease