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. Tome, 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 journalArticleAcademicpeer-review

30 Citations (Web of Science)

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.

Original languageEnglish
Article number16058
Number of pages12
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 13 Jul 2017

Keywords

  • DNA-BINDING PROTEINS
  • HUMAN CELL-TYPES
  • THROMBUS FORMATION
  • GENE-REGULATION
  • OPEN CHROMATIN
  • TRAIT LOCI
  • DISEASE
  • SEQ
  • GENOME
  • BLOOD

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