Platelet function is modified by common sequence variation in megakaryocyte super enhancers

Romina Petersen, John J. Lambourne, Biola M. Javierre, Luigi Grassi, Roman Kreuzhuber, Dace Ruklisa, Isabel M. Rosa, Ana R. Tomé, Heather Elding, Johanna P. Van Geffen, Tao Jiang, Samantha Farrow, Jonathan Cairns, Abeer M. Al-Subaie, Sofie Ashford, Antony Attwood, Joana Batista, Heleen Bouman, Frances Burden, Fizzah A. ChoudryLaura Clarke, Paul Flicek, Stephen F. Garner, Matthias Haimel, Carly Kempster, Vasileios Ladopoulos, An Sofie Lenaerts, Paulina M. Materek, Harriet McKinney, Stuart Meacham, Daniel Mead, Magdolna Nagy, Christopher J. Penkett, Augusto Rendon, Denis Seyres, Benjamin Sun, Salih Tuna, Marie Elise Van Der Weide, Steven W. Wingett, Joost H. Martens, Oliver Stegle, Sylvia Richardson, Ludovic Vallier, David J. Roberts, Kathleen Freson, Lorenz Wernisch, Hendrik G. Stunnenberg, John Danesh, Peter Fraser, Nicole Soranzo, Adam S. Butterworth, Johan W. Heemskerk, Ernest Turro, Mikhail Spivakov, Willem H. Ouwehand, William J. Astle, Kate Downes, Myrto Kostadima, Mattia Frontini*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


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 identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.

Original languageEnglish
Article number16058
JournalNature Communications
Publication statusPublished - 13 Jul 2017
Externally publishedYes

Bibliographical note

Funding Information:
We gratefully acknowledge the participation of National Institute of Health Research (NIHR) Cambridge BioResource volunteers and thank the NIHR Cambridge BioResource staff for their support for the recall study of genotyped subjects. 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 a HTSS trainee supported by NHS Health Education England; M.F. is supported by the British Heart Foundation (BHF) Cambridge Centre of Excellence (RE/13/6/30180); D.S. is funded by an Isaac Newton fellowship to M.F.; 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). R.P. is supported by the European Union's Horizon 2020 research and innovation programme under grant agreement number 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. Fraser 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. Flicek and from the European Molecular Biology Laboratory to L.C., M.K., P. Flicek 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. 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.


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