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. Choudry, Laura 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 () and Mattia Frontini ()
Additional contact information
Romina Petersen: University of Cambridge
John J. Lambourne: University of Cambridge
Biola M. Javierre: Nuclear Dynamics Programme, The Babraham Institute
Luigi Grassi: University of Cambridge
Roman Kreuzhuber: University of Cambridge
Dace Ruklisa: University of Cambridge
Isabel M. Rosa: University of Cambridge
Ana R. Tomé: University of Cambridge
Heather Elding: The Wellcome Trust Sanger Institute
Johanna P. van Geffen: Cardiovascular Research Institute Maastricht, Maastricht University
Tao Jiang: Strangeways Research Laboratory, MRC/British Heart Foundation (BHF) Cardiovascular Epidemiology Unit, University of Cambridge
Samantha Farrow: University of Cambridge
Jonathan Cairns: Nuclear Dynamics Programme, The Babraham Institute
Abeer M. Al-Subaie: University of Cambridge
Sofie Ashford: University of Cambridge
Antony Attwood: University of Cambridge
Joana Batista: University of Cambridge
Heleen Bouman: The Wellcome Trust Sanger Institute
Frances Burden: University of Cambridge
Fizzah A. Choudry: University of Cambridge
Laura Clarke: European Molecular Biology Laboratory, European Bioinformatics Institute
Paul Flicek: European Molecular Biology Laboratory, European Bioinformatics Institute
Stephen F. Garner: National Health Service Blood and Transplant (NHSBT)
Matthias Haimel: NIHR BioResource-Rare Diseases, University of Cambridge
Carly Kempster: University of Cambridge
Vasileios Ladopoulos: University of Cambridge
An-Sofie Lenaerts: NIHR Cambridge Biomedical Research Centre hIPSC Core Facility, University of Cambridge
Paulina M. Materek: NIHR Cambridge Biomedical Research Centre hIPSC Core Facility, University of Cambridge
Harriet McKinney: University of Cambridge
Stuart Meacham: University of Cambridge
Daniel Mead: The Wellcome Trust Sanger Institute
Magdolna Nagy: Cardiovascular Research Institute Maastricht, Maastricht University
Christopher J. Penkett: University of Cambridge
Augusto Rendon: University of Cambridge
Denis Seyres: University of Cambridge
Benjamin Sun: Strangeways Research Laboratory, MRC/British Heart Foundation (BHF) Cardiovascular Epidemiology Unit, University of Cambridge
Salih Tuna: University of Cambridge
Marie-Elise van der Weide: University of Cambridge
Steven W. Wingett: Nuclear Dynamics Programme, The Babraham Institute
Joost H. Martens: Faculty of Science, Radboud University
Oliver Stegle: European Molecular Biology Laboratory, European Bioinformatics Institute
Sylvia Richardson: Medical Research Council Biostatistics Unit, University of Cambridge
Ludovic Vallier: Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge
David J. Roberts: John Radcliffe Hospital, University of Oxford
Kathleen Freson: Center for Molecular and Vascular Biology, University of Leuven
Lorenz Wernisch: Medical Research Council Biostatistics Unit, University of Cambridge
Hendrik G. Stunnenberg: Faculty of Science, Radboud University
John Danesh: The Wellcome Trust Sanger Institute
Peter Fraser: Nuclear Dynamics Programme, The Babraham Institute
Nicole Soranzo: University of Cambridge
Adam S. Butterworth: Strangeways Research Laboratory, The National Institute for Health Research (NIHR) Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, University of Cambridge
Johan W. Heemskerk: Cardiovascular Research Institute Maastricht, Maastricht University
Ernest Turro: University of Cambridge
Mikhail Spivakov: Nuclear Dynamics Programme, The Babraham Institute
Willem H. Ouwehand: University of Cambridge
William J. Astle: University of Cambridge
Kate Downes: University of Cambridge
Myrto Kostadima: University of Cambridge
Mattia Frontini: University of Cambridge

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms16058

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