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. 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

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 journal › Article › Academic › peer-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 language	English
Article number	16058
Number of pages	12
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms16058
Publication status	Published - 13 Jul 2017

Keywords

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

Access to Document

10.1038/ncomms16058

Cite this

Petersen, R., Lambourne, J. J., Javierre, B. M., Grassi, L., Kreuzhuber, R., Ruklisa, D., Rosa, I. M., Tome, A. R., Elding, H., van Geffen, J. P., Jiang, T., Farrow, S., Cairns, J., Al-Subaie, A. M., Ashford, S., Attwood, A., Batista, J., Bouman, H., Burden, F., ... Frontini, M. (2017). Platelet function is modified by common sequence variation in megakaryocyte super enhancers. Nature Communications, 8, [16058]. https://doi.org/10.1038/ncomms16058

@article{40b64b3758f94da7bf4af89b0abcb547,

title = "Platelet function is modified by common sequence variation in megakaryocyte super enhancers",

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.",

keywords = "DNA-BINDING PROTEINS, HUMAN CELL-TYPES, THROMBUS FORMATION, GENE-REGULATION, OPEN CHROMATIN, TRAIT LOCI, DISEASE, SEQ, GENOME, BLOOD",

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

year = "2017",

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day = "13",

doi = "10.1038/ncomms16058",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

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Petersen, R, Lambourne, JJ, Javierre, BM, Grassi, L, Kreuzhuber, R, Ruklisa, D, Rosa, IM, Tome, AR, Elding, H, van Geffen, JP, Jiang, T, Farrow, S, Cairns, J, Al-Subaie, AM, Ashford, S, Attwood, A, Batista, J, Bouman, H, Burden, F, Choudry, FA, Clarke, L, Flicek, P, Garner, SF, Haimel, M, Kempster, C, Ladopoulos, V, Lenaerts, A-S, Materek, PM, McKinney, H, Meacham, S, Mead, D, Nagy, M, Penkett, CJ, Rendon, A, Seyres, D, Sun, B, Tuna, S, van der Weide, M-E, Wingett, SW, Martens, JH, Stegle, O, Richardson, S, Vallier, L, Roberts, DJ, Freson, K, Wernisch, L, Stunnenberg, HG, Danesh, J, Fraser, P, Soranzo, N, Butterworth, AS, Heemskerk, JW, Turro, E, Spivakov, M, Ouwehand, WH, Astle, WJ, Downes, K, Kostadima, M & Frontini, M 2017, 'Platelet function is modified by common sequence variation in megakaryocyte super enhancers', Nature Communications, vol. 8, 16058. https://doi.org/10.1038/ncomms16058

TY - JOUR

T1 - Platelet function is modified by common sequence variation in megakaryocyte super enhancers

AU - Petersen, Romina

AU - Lambourne, John J.

AU - Javierre, Biola M.

AU - Grassi, Luigi

AU - Kreuzhuber, Roman

AU - Ruklisa, Dace

AU - Rosa, Isabel M.

AU - Tome, Ana R.

AU - Elding, Heather

AU - van Geffen, Johanna P.

AU - Jiang, Tao

AU - Farrow, Samantha

AU - Cairns, Jonathan

AU - Al-Subaie, Abeer M.

AU - Ashford, Sofie

AU - Attwood, Antony

AU - Batista, Joana

AU - Bouman, Heleen

AU - Burden, Frances

AU - Choudry, Fizzah A.

AU - Clarke, Laura

AU - Flicek, Paul

AU - Garner, Stephen F.

AU - Haimel, Matthias

AU - Kempster, Carly

AU - Ladopoulos, Vasileios

AU - Lenaerts, An-Sofie

AU - Materek, Paulina M.

AU - McKinney, Harriet

AU - Meacham, Stuart

AU - Mead, Daniel

AU - Nagy, Magdolna

AU - Penkett, Christopher J.

AU - Rendon, Augusto

AU - Seyres, Denis

AU - Sun, Benjamin

AU - Tuna, Salih

AU - van der Weide, Marie-Elise

AU - Wingett, Steven W.

AU - Martens, Joost H.

AU - Stegle, Oliver

AU - Richardson, Sylvia

AU - Vallier, Ludovic

AU - Roberts, David J.

AU - Freson, Kathleen

AU - Wernisch, Lorenz

AU - Stunnenberg, Hendrik G.

AU - Danesh, John

AU - Fraser, Peter

AU - Soranzo, Nicole

AU - Butterworth, Adam S.

AU - Heemskerk, Johan W.

AU - Turro, Ernest

AU - Spivakov, Mikhail

AU - Ouwehand, Willem H.

AU - Astle, William J.

AU - Downes, Kate

AU - Kostadima, Myrto

AU - Frontini, Mattia

PY - 2017/7/13

Y1 - 2017/7/13

N2 - 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.

AB - 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.

KW - DNA-BINDING PROTEINS

KW - HUMAN CELL-TYPES

KW - THROMBUS FORMATION

KW - GENE-REGULATION

KW - OPEN CHROMATIN

KW - TRAIT LOCI

KW - DISEASE

KW - SEQ

KW - GENOME

KW - BLOOD

U2 - 10.1038/ncomms16058

DO - 10.1038/ncomms16058

M3 - Article

C2 - 28703137

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 16058

ER -