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

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 journal › Article › peer-review

34 Citations (Scopus)

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
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms16058
Publication status	Published - 13 Jul 2017
Externally published	Yes

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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Petersen, R., Lambourne, J. J., Javierre, B. M., Grassi, L., Kreuzhuber, R., Ruklisa, D., Rosa, I. M., Tomé, 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{459205763e034160b4da91837a024491,

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.",

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 Tom{\'e}, {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 Lenaerts, {An Sofie} 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",

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.",

year = "2017",

month = jul,

day = "13",

doi = "10.1038/ncomms16058",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Petersen, R, Lambourne, JJ, Javierre, BM, Grassi, L, Kreuzhuber, R, Ruklisa, D, Rosa, IM, Tomé, 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, AS, Materek, PM, McKinney, H, Meacham, S, Mead, D, Nagy, M, Penkett, CJ, Rendon, A, Seyres, D, Sun, B, Tuna, S, Van Der Weide, ME, 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 - Tomé, 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

N1 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85024114239&partnerID=8YFLogxK

U2 - 10.1038/ncomms16058

DO - 10.1038/ncomms16058

M3 - Article

C2 - 28703137

AN - SCOPUS:85024114239

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 16058

ER -

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

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