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; Mattia Frontini

doi:10.1038/ncomms16058

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

Nat Commun. 2017 Jul 13:8:16058. doi: 10.1038/ncomms16058.

Authors

Romina Petersen^{1

2}, John J Lambourne^{1

2}, Biola M Javierre³, Luigi Grassi^{1

2

4}, Roman Kreuzhuber^{1

2

5}, Dace Ruklisa^{1

2

6}, Isabel M Rosa^{1

2}, Ana R Tomé^{1

2}, Heather Elding^{7

8}, Johanna P van Geffen⁹, Tao Jiang¹⁰, Samantha Farrow^{1

2}, Jonathan Cairns³, Abeer M Al-Subaie^{1

2

11}, Sofie Ashford^{1

2

4}, Antony Attwood^{1

2

4}, Joana Batista^{1

2}, Heleen Bouman⁷, Frances Burden^{1

2}, Fizzah A Choudry^{1

2}, Laura Clarke⁵, Paul Flicek⁵, Stephen F Garner², Matthias Haimel^{4

12}, Carly Kempster^{1

2}, Vasileios Ladopoulos¹, An-Sofie Lenaerts^{13

14}, Paulina M Materek^{13

14}, Harriet McKinney^{1

2}, Stuart Meacham^{1

2

4}, Daniel Mead⁷, Magdolna Nagy⁹, Christopher J Penkett^{1

2

4}, Augusto Rendon^{1

2

15}, Denis Seyres^{1

2

4}, Benjamin Sun¹⁰, Salih Tuna^{1

2

4}, Marie-Elise van der Weide^{1

2}, Steven W Wingett³, Joost H Martens¹⁶, Oliver Stegle⁵, Sylvia Richardson⁶, Ludovic Vallier^{14

17}, David J Roberts^{18

19

20}, Kathleen Freson²¹, Lorenz Wernisch⁶, Hendrik G Stunnenberg¹⁶, John Danesh^{7

8

10

22}, Peter Fraser^{3

23}, Nicole Soranzo^{1

7

8

22}, Adam S Butterworth^{8

10

22}, Johan W Heemskerk⁹, Ernest Turro^{1

2

4

6}, Mikhail Spivakov³, Willem H Ouwehand^{1

2

7

8

22}, William J Astle^{1

2

6

10

22}, Kate Downes^{1

2}, Myrto Kostadima^{1

2

5}, Mattia Frontini^{1

2

22}

Affiliations

¹ Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
² National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
³ Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
⁴ NIHR BioResource-Rare Diseases, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
⁵ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
⁶ Medical Research Council Biostatistics Unit, University of Cambridge, Forvie Site, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
⁷ Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
⁸ 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, Cambridge CB1 8RN, UK.
⁹ Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
¹⁰ Strangeways Research Laboratory, MRC/British Heart Foundation (BHF) Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
¹¹ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Dammam, P.O. Box 1982, Dammam 31441, Saudi Arabia.
¹² Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹³ NIHR Cambridge Biomedical Research Centre hIPSC Core Facility, Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK.
¹⁴ Wellcome Trust and MRC Cambridge Stem Cell Institute, Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK.
¹⁵ Genomics England Limited, Queen Mary University of London, Dawson Hall, London EC1M 6BQ, UK.
¹⁶ Faculty of Science, Department of Molecular Biology, Radboud University, 6525GA Nijmegen, The Netherlands.
¹⁷ The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
¹⁸ Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX9 3DU, UK.
¹⁹ Department of Haematology, Churchill Hospital, Headington, Oxford OX3 7LE, UK.
²⁰ NHSBT, John Radcliffe Hospital, Headington, Oxford OX3 9BQ, UK.
²¹ Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven 3000, Belgium.
²² BHF Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
²³ Department of Biological Science, Florida State University, Tallahassee, Florida 32303, USA.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blood Platelets / physiology*
Chromatin
Enhancer Elements, Genetic*
Erythroblasts / chemistry*
Genetic Variation*
Humans
Megakaryocytes / chemistry*
Promoter Regions, Genetic

Substances

Chromatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding