Cell
Volume 182, Issue 5, 3 September 2020, Pages 1214-1231.e11
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Article
The Polygenic and Monogenic Basis of Blood Traits and Diseases

https://doi.org/10.1016/j.cell.2020.08.008Get rights and content
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Highlights

  • Largest genome-wide association study of blood cell traits to date

  • Empiric assessments of omnigenic and infinitesimal models of polygenic variation

  • Functional insights into how genetic variants impact human hematopoiesis

  • Assessment of the effect of polygenic trait scores upon blood diseases

Summary

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.

Keywords

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

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A list of members and their affiliations appears in the Extended Acknowledgments and Author Contributions

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These authors contributed equally

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These authors contributed equally

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