The Polygenic and Monogenic Basis of Blood Traits and Diseases
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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.
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Before the analyses, blood cell measures from individuals with extreme values or relevant medical conditions were excluded following previously described methods.
“Before the analyses, we followed the previously described methods 63 to exclude blood cell measures from individuals with extreme values or relevant medical conditions.”
From Plasma proteomic associations with genetics and health in the UK Biobank (2023) · cites this paper as [63]
Population-based genetic variation has largely been studied for blood cell traits, and over ten thousand loci have been defined across the allelic spectrum that explain inter-individual variation in such traits.
“Population-based genetic variation has largely been studied for blood cell traits, and over ten thousand loci have been defined across the allelic spectrum that explain inter-individual variation in such traits (Astle et al., 2016; Chen et al., 2020; Vuckovic et al., 2020).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Vuckovic et al., 2020
The emerging picture is that a spectrum of polygenic variation and large-effect monogenic variants collectively influence hematopoiesis to shape one's risk of having a blood disorder or altered hematopoiesis.
“The emerging picture is therefore that a spectrum of polygenic variation and large-effect monogenic variants collectively influence hematopoiesis to shape one’s risk of having a blood disorder or altered hematopoiesis (Vuckovic et al., 2020).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Vuckovic et al., 2020
The ability to fine-map variants associated with blood cell traits and overlap these variants with accessible chromatin in hematopoietic progenitors has provided unprecedented insight into how genetic variation can influence a range of cell states in hematopoiesis.
“In addition, the ability to fine-map variants associated with blood cell traits and overlap these variants with accessible chromatin in hematopoietic progenitors has provided unprecedented insight into how genetic variation can influence a range of cell states in hematopoiesis (Ulirsch et al., 2019; Vuckovic et al., 2020).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Vuckovic et al., 2020
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Marderstein, A. R., De Zuani, M., Moeller, R., Bezney, J., Padhi, E. M., Wong, S., Coorens, T. H. H., Xie, Y., Xue, H., Montgomery, S. B., et al. (2024) · Nature · doi:10.1038/s41586-024-07946-4 · Cited by 26 · see citing works
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Examining the genetic links between clusters of immune-mediated diseases and psychiatric disorders
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- Authors
- Vuckovic, D., Bao, E. L., Akbari, P., Lareau, C. A., Mousas, A., Jiang, T., Chen, M.-H., Raffield, L. M., Tardaguila, M., Huffman, J. E., Ritchie, S. C., Megy, K., Ponstingl, H., Penkett, C. J., Albers, P. K., Wigdor, E. M., Sakaue, S., Moscati, A., Manansala, R., Lo, K. S., Qian, H., Akiyama, M., Bartz, T. M., Ben-Shlomo, Y., Beswick, A., Bork-Jensen, J., Bottinger, E. P., Brody, J. A., van Rooij, F. J. A., Chitrala, K. N., Wilson, P. W. F., Choquet, H., Danesh, J., Di Angelantonio, E., Dimou, N., Ding, J., Elliott, P., Esko, T., Evans, M. K., Felix, S. B., Floyd, J. S., Broer, L., Grarup, N., Guo, M. H., Guo, Q., Greinacher, A., Haessler, J., Hansen, T., Howson, J. M. M., Huang, W., Jorgenson, E., Kacprowski, T., Kähönen, M., Kamatani, Y., Kanai, M., Karthikeyan, S., Koskeridis, F., Lange, L. A., Lehtimäki, T., Linneberg, A., Liu, Y., Lyytikäinen, L.-P., Manichaikul, A., Matsuda, K., Mohlke, K. L., Mononen, N., Murakami, Y., Nadkarni, G. N., Nikus, K., Pankratz, N., Pedersen, O., Preuss, M., Psaty, B. M., Raitakari, O. T., Rich, S. S., Rodriguez, B. A. T., Rosen, J. D., Rotter, J. I., Schubert, P., Spracklen, C. N., Surendran, P., Tang, H., Tardif, J.-C., Ghanbari, M., Völker, U., Völzke, H., Watkins, N. A., Weiss, S., Cai, N., Kundu, K., Watt, S. B., Walter, K., Zonderman, A. B., Cho, K., Li, Y., Loos, R. J. F., Knight, J. C., Georges, M., Stegle, O., Evangelou, E., Okada, Y., Roberts, D. J., Inouye, M., Johnson, A. D., Auer, P. L., Astle, W. J., Reiner, A. P., Butterworth, A. S., Ouwehand, W. H., Lettre, G., Sankaran, V. G., & Soranzo, N.
- Affiliations
- University of Cambridge (GB)
- Broad Institute (US)
- Montreal Heart Institute (CA)
- National Heart, Lung, and Blood Institute (US)
- University of North Carolina at Chapel Hill (US)
- VA Boston Healthcare System (US)
- Baker Heart and Diabetes Institute (AU)
- Wellcome Sanger Institute (GB)
- RIKEN Center for Integrative Medical Sciences (JP)
- Icahn School of Medicine at Mount Sinai (US)
- University of Wisconsin–Milwaukee (US)
- Kyushu University (JP)
- University of Washington (US)
- University of Bristol (GB)
- National Institutes of Health (US)
- Atlanta VA Medical Center (US)
- Kaiser Permanente (US)
- University of Ioannina (GR)
- Wake Forest University Health Sciences (US)
- Imperial College Healthcare NHS Trust (GB)
- Universitätsmedizin Greifswald (DE)
- Erasmus MC (NL)
- University of Copenhagen (DK)
- Fred Hutch Cancer Center (US)
- Chinese National Human Genome Center (CN)
- Tampere University (FI)
- Massachusetts General Hospital (US)
- University of Colorado Anschutz (US)
- Duke University (US)
- University of Virginia (US)
- The University of Tokyo (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- University of Minnesota (US)
- Kaiser Permanente Washington Health Research Institute (US)
- University of Turku (FI)
- The Lundquist Institute (US)
- Stanford Medicine (US)
- Mashhad University of Medical Sciences (IR)
- National Health Service (GB)
- Brigham and Women's Hospital (US)
- Centre for Human Genetics (GB)
- University of Liège (BE)
- European Bioinformatics Institute (GB)
- The University of Osaka (JP)
- NHS Blood and Transplant (GB)
- Corresponding author
- Sankaran, Vijay G.
- Soranzo, Nicole
- ORCID
- Vuckovic, Dragana
- Bao, Erik L.
- Akbari, Parsa
- Lareau, Caleb A.
- Mousas, Abdou
- Chen, Ming-Huei
- Raffield, Laura M.
- Huffman, Jennifer E.
- Ritchie, Scott C.
- Megy, Karyn
- Ponstingl, Hannes
- Penkett, Christopher J.
- Albers, Patrick K.
- Wigdor, Emilie M.
- Sakaue, Saori
- Moscati, Arden
- Manansala, Regina
- Lo, Ken Sin
- Qian, Huijun
- Akiyama, Masato
- Bartz, Traci M.
- Ben-Shlomo, Yoav
- Beswick, Andrew
- Bottinger, Erwin P.
- Brody, Jennifer A.
- Chitrala, Kumaraswamy N.
- Wilson, Peter W.F.
- Choquet, Hélène
- Danesh, John
- Dimou, Niki
- Ding, Jingzhong
- Elliott, Paul
- Esko, Tõnu
- Evans, Michele K.
- Felix, Stephan B.
- Floyd, James S.
- Broer, Linda
- Grarup, Niels
- Guo, Michael H.
- Guo, Qi
- Greinacher, Andreas
- Hansen, Torben
- Howson, Joanna M.M.
- Huang, Wei
- Jorgenson, Eric
- Kacprowski, Tim
- Kähönen, Mika
- Kanai, Masahiro
- Karthikeyan, Savita
- Koskeridis, Fotios
- Lange, Leslie A.
- Lehtimäki, Terho
- Linneberg, Allan
- Liu, Yongmei
- Lyytikäinen, Leo-Pekka
- Manichaikul, Ani
- Matsuda, Koichi
- Mohlke, Karen L.
- Mononen, Nina
- Nadkarni, Girish N.
- Nikus, Kjell
- Pankratz, Nathan
- Pedersen, Oluf
- Preuss, Michael
- Psaty, Bruce M.
- Raitakari, Olli T.
- Rich, Stephen S.
- Rodriguez, Benjamin A.T.
- Rosen, Jonathan D.
- Rotter, Jerome I.
- Schubert, Petra
- Spracklen, Cassandra N.
- Surendran, Praveen
- Tang, Hua
- Tardif, Jean-Claude
- Ghanbari, Mohsen
- Völker, Uwe
- Völzke, Henry
- Weiss, Stefan
- Cai, Na
- Kundu, Kousik
- Watt, Stephen B.
- Walter, Klaudia
- Zonderman, Alan B.
- Cho, Kelly
- Li, Yun
- Loos, Ruth J.F.
- Knight, Julian C.
- Georges, Michel
- Stegle, Oliver
- Okada, Yukinori
- Roberts, David J.
- Inouye, Michael
- Johnson, Andrew D.
- Auer, Paul L.
- Astle, William J.
- Butterworth, Adam S.
- Ouwehand, Willem H.
- Lettre, Guillaume
- Sankaran, Vijay G.
- Soranzo, Nicole
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 182
- Issue
- 5
- Pages
- 1214-1231.e11
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7482360
- OpenAlex
- W3081528139
- Cited by
- 671
- References
- 81
- Citations by year
- 2026: 81 · 2025: 131 · 2024: 149 · 2023: 118 · 2022: 108 · 2021: 75 · 2020: 8 · 2018: 1
- FWCI
- 11.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- publish.UP (University of Potsdam) (submittedVersion, cc-by)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- ORBi (University of Liège) (submittedVersion, other-oa)
- Scopus (Elsevier) (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- National Institute for Health Research
- National Institutes of Health
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- hematopoiesis, polygenic architecture, monogenic disorders, genetic variants, omnigenic model, splice-altering variants, gene networks, polygenic prediction, blood characteristics, European ancestry
- MeSH terms
- Female, Hematopoiesis, Humans, Male, Phenotype, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Gene Regulatory Networks, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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