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The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Published version
Peer-reviewed

Change log

Authors

Astle, WJ 
Elding, H 
Jiang, T 
Allen, D 
Ruklisa, D 

Abstract

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.

Description

Keywords

blood, genetics, hematology, epigenetics, hematopoiesis, Mendelian randomization, complex disease, autoimmune diseases, cardiovascular diseases

Journal Title

Cell

Conference Name

Journal ISSN

0092-8674
1097-4172

Volume Title

167

Publisher

Elsevier
Sponsorship
Medical Research Council (G0800270)
European Research Council (268834)
European Commission (257082)
British Heart Foundation (None)
Medical Research Council (MR/P02811X/1)
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (116074)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
British Heart Foundation (CH/12/2/29428)
Medical Research Council (MR/P013880/1)
Ume� University (unknown)
NHS Blood and Transplant (NHSBT) (WP12-01)
European Commission (279143)
NHS Blood and Transplant (NHSBT) (11-01-GEN)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
British Heart Foundation (None)
Medical Research Council (MR/L003120/1)
European Commission (279233)
MRC (MR/J015709/1)
MRC (MR/J006602/1)
MRC (MR/J006599/1)
Medical Research Council (MR/M012816/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
British Heart Foundation (RG/16/4/32218)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-25)
Department of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10024)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1516-29)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
European Commission FP7 Network of Excellence (NoE) (282510)
Wellcome Trust (091310/Z/10/Z)
British Heart Foundation (None)
CCF (None)
Medical Research Council (G0800270/1)
We thank members of the Cambridge BioResource Scientific Advisory Board and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. K.D. is funded as a HSST trainee by NHS Health Education England. M.F. is funded from the BLUEPRINT Grant Code HEALTH-F5-2011-282510 and the BHF Cambridge Centre of Excellence [RE/13/6/30180]. J.R.S. is funded by a MRC CASE Industrial studentship, co-funded by Pfizer. J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. S.M., S.T, M.H, K.M. and L.D. are supported by the NIHR BioResource-Rare Diseases, which is funded by NIHR. Research in the Ouwehand laboratory is supported by program grants from the NIHR to W.H.O., the European Commission (HEALTH-F2-2012-279233), the British Heart Foundation (BHF) to W.J.A. and D.R. under numbers RP-PG-0310-1002 and RG/09/12/28096 and Bristol Myers-Squibb; the laboratory also receives funding from NHSBT. W.H.O is a NIHR Senior Investigator. The INTERVAL academic coordinating centre receives core support from the UK Medical Research Council (G0800270), the BHF (SP/09/002), the NIHR and Cambridge Biomedical Research Centre, as well as grants from the European Research Council (268834), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), Merck and Pfizer. DJR and DA were supported by the NIHR Programme ‘Erythropoiesis in Health and Disease’ (Ref. NIHR-RP-PG-0310-1004). N.S. is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510). The INTERVAL study is funded by NHSBT and has been supported by the NIHR-BTRU in Donor Health and Genomics at the University of Cambridge in partnership with NHSBT. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health of England or NHSBT. D.G. is supported by a “la Caixa”-Severo Ochoa pre-doctoral fellowship.