Platelet function is modified by common sequence variation in megakaryocyte super enhancers
Mapping platelet trait associated variants with DNA long-range interactions reveals super enhancer role in thrombosis
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Petersen, R. (2017). Platelet function is modified by common sequence variation in megakaryocyte super enhancers. Nature Communications, 8 (16058)https://doi.org/10.1038/ncomms16058
Linking non-coding genetic variants associated with the risk of diseases or disease relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type matched epigenomic data and promoter long-range interactions. We identified potential regulatory functions for 423 of 565 (75%) non-coding platelet variants and highlighted, including ex vivo and genome editing proof of principle validation, the role of associated variants in super enhancers in controlling archetypical platelet functions.
The work was funded by a grant from the European Commission 7th Framework Program (FP7/2007-2013, grant 282510, BLUEPRINT). F.A.C. is a Medical Research Council (MRC) clinical fellow (MR/K024043/1); K.D. is funded by NHS Health Education England; M.F. is supported by the British Heart Foundation (BHF) Cambridge Centre of Excellence (RE/13/6/30180); research in the W.H.O. laboratory is also supported by grants from Bristol Myers-Squibb, BHF, European Commission, MRC, NIHR (W.H.O. is NIHR Senior Investigator) and NHS Blood and Transplant (NHSBT). RP is supported by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 692041 (TrainMALTA, H2020-TWINN-2015). L.V. is funded by the ERC grant Relieve IMDs (ERC-2011-StG). P.M. and A-S.L. are funded by the NIHR Cambridge Biomedical Research Centre (BRC) hIPSCs core facility. B.M.J., P.Fr. and M.S. are supported by the MRC (MR/L007150/1) and Biotechnology and Biological Sciences Research Council (BB/J004480/1). K.F. is funded by FWO-Vlaanderen (G.0B17.13N) and BOF KULeuven (OT/14/098). Work at EMBL-EBI received additional support from the Wellcome Trust (WT095908) to P.Fl and from the European Molecular Biology Laboratory to L.C., M.K., P.Fl. and O.S. The MRC/BHF Cardiovascular Epidemiology receives core support from the MRC (G0800270), the BHF (SP/09/002), the NIHR and NIHR Cambridge BRC, as well as grants from the European Research Council (268834), the European Commission FP7 (HEALTH-F2-2012-279233), Merck and Pfizer. J.D. is a BHF Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. The NIHR Blood and Transplant Research Unit in Donor Health and Genomics at the University of Cambridge is funded by NIHR and NHSBT.
External DOI: https://doi.org/10.1038/ncomms16058
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266539
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/