The Polygenic and Monogenic Basis of Blood Traits and Diseases

Dragana Vuckovic, Erik L. Bao, Parsa Akbari, Caleb A. Lareau, Abdou Mousas, Tao Jiang, Ming Huei Chen, Laura M. Raffield, Manuel Tardaguila, Jennifer E. Huffman, Scott C. Ritchie, Karyn Megy, Hannes Ponstingl, Christopher J. Penkett, Patrick K. Albers, Emilie M. Wigdor, Saori Sakaue, Arden Moscati, Regina Manansala, Ken Sin LoHuijun Qian, Masato Akiyama, Traci M. Bartz, Yoav Ben-Shlomo, Andrew Beswick, Jette Bork-Jensen, Erwin P. Bottinger, Jennifer A. Brody, Frank J.A. van Rooij, Kumaraswamy N. Chitrala, Peter W.F. Wilson, Hélène Choquet, John Danesh, Emanuele Di Angelantonio, Niki Dimou, Jingzhong Ding, Paul Elliott, Tõnu Esko, Michele K. Evans, Stephan B. Felix, James S. Floyd, Linda Broer, Niels Grarup, Michael H. Guo, Qi Guo, Andreas Greinacher, Jeff Haessler, Torben Hansen, Joanna M.M. Howson, Wei Huang, Eric Jorgenson, Tim Kacprowski, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Savita Karthikeyan, Fotios Koskeridis, Leslie A. Lange, Terho Lehtimäki, Allan Linneberg, Yongmei Liu, Leo Pekka Lyytikäinen, Ani Manichaikul, Koichi Matsuda, Karen L. Mohlke, Nina Mononen, Yoshinori Murakami, Girish N. Nadkarni, Kjell Nikus, Nathan Pankratz, Oluf Pedersen, Michael Preuss, Bruce M. Psaty, Olli T. Raitakari, Stephen S. Rich, Benjamin A.T. Rodriguez, Jonathan D. Rosen, Jerome I. Rotter, Petra Schubert, Cassandra N. Spracklen, Praveen Surendran, Hua Tang, Jean Claude Tardif, Mohsen Ghanbari, Uwe Völker, Henry Völzke, Nicholas A. Watkins, Stefan Weiss, Na Cai, Kousik Kundu, Stephen B. Watt, Klaudia Walter, Alan B. Zonderman, Kelly Cho, Yun Li, Ruth J.F. Loos, Julian C. Knight, Michel Georges, Oliver Stegle, Evangelos Evangelou, Yukinori Okada, David J. Roberts, Michael Inouye, Andrew D. Johnson, Paul L. Auer, William J. Astle, Alexander P. Reiner, Adam S. Butterworth, Willem H. Ouwehand, Guillaume Lettre, Vijay G. Sankaran, Nicole Soranzo

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1214-1231.e11
JournalCell
Volume182
Issue number5
DOIs
StatePublished - Sep 3 2020

Bibliographical note

Funding 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.

Publisher Copyright:
© 2020 The Authors

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • UK Biobank
  • blood
  • chromatin
  • fine-mapping
  • genetics
  • hematopoiesis
  • omnigenic
  • polygenic risk
  • rare disease
  • splicing

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