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A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology.

Published version
Peer-reviewed

Repository DOI


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Authors

Vuckovic, Dragana 
Jiang, Tao 

Abstract

Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes-including cell-type specific measures of granularity, nucleic acid content and reactivity-in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types-variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.

Description

Keywords

Causality, Genome-Wide Association Study, Microscopy, Proteomics, Transcription Factors

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

14

Publisher

Nature Portfolio
Sponsorship
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (CH/12/2/29428)
Medical Research Council (MR/P02002X/1)
Medical Research Council (MR/S004068/1)
British Heart Foundation (RG/18/13/33946)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MC_UU_00002/7)