Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

Harri Lempiäinen; Ingrid Brænne; Tom Michoel; Vinicius Tragante; Baiba Vilne; Tom R. Webb; Theodosios Kyriakou; Johannes Eichner; Lingyao Zeng; Christina Willenborg; Oscar Franzen; Arno Ruusalepp; Anuj Goel; Sander W. Van Der Laan; Claudia Biegert; Stephen Hamby; Husain A. Talukdar; Hassan Foroughi Asl; Martin Dichgans; Tobias Dreker; Mira Graettinger; Philip Gribbon; Thorsten Kessler; Rainer Malik; Matthias Prestel; Barbara Stiller; Christine Schofield; Gerard Pasterkamp; Hugh Watkins; Nilesh J. Samani; Timo Wittenberger; Jeanette Erdmann; Heribert Schunkert; Folkert W. Asselbergs; Johan L.M. Björkegren

doi:10.1038/s41598-018-20721-6

Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

Harri Lempiäinen, Ingrid Brænne, Tom Michoel, Vinicius Tragante, Baiba Vilne, Tom R. Webb, Theodosios Kyriakou, Johannes Eichner, Lingyao Zeng, Christina Willenborg, Oscar Franzen, Arno Ruusalepp, Anuj Goel, Sander W. Van Der Laan, Claudia Biegert, Stephen Hamby, Husain A. Talukdar, Hassan Foroughi Asl, Martin Dichgans, Tobias DrekerMira Graettinger, Philip Gribbon, Thorsten Kessler, Rainer Malik, Matthias Prestel, Barbara Stiller, Christine Schofield, Gerard Pasterkamp, Hugh Watkins, Nilesh J. Samani, Timo Wittenberger, Jeanette Erdmann, Heribert Schunkert, Folkert W. Asselbergs, Johan L.M. Björkegren

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Abstract

Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.

Original language	English
Article number	3434
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-20721-6
Publication status	Published - 1 Dec 2018
Externally published	Yes

Field of Science*

3.2 Clinical medicine
3.1 Basic medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

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10.1038/s41598-018-20721-6

Network analysis of coronaryFinal published version, 2.25 MB

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Lempiäinen, H., Brænne, I., Michoel, T., Tragante, V., Vilne, B., Webb, T. R., Kyriakou, T., Eichner, J., Zeng, L., Willenborg, C., Franzen, O., Ruusalepp, A., Goel, A., Van Der Laan, S. W., Biegert, C., Hamby, S., Talukdar, H. A., Foroughi Asl, H., Dichgans, M., ... Björkegren, J. L. M. (2018). Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets. Scientific Reports, 8(1), Article 3434. https://doi.org/10.1038/s41598-018-20721-6

@article{722576e8413847ab95224644cbbc94c7,

title = "Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets",

abstract = "Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ({"}modules{"}). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.",

author = "Harri Lempi{\"a}inen and Ingrid Br{\ae}nne and Tom Michoel and Vinicius Tragante and Baiba Vilne and Webb, {Tom R.} and Theodosios Kyriakou and Johannes Eichner and Lingyao Zeng and Christina Willenborg and Oscar Franzen and Arno Ruusalepp and Anuj Goel and {Van Der Laan}, {Sander W.} and Claudia Biegert and Stephen Hamby and Talukdar, {Husain A.} and {Foroughi Asl}, Hassan and Martin Dichgans and Tobias Dreker and Mira Graettinger and Philip Gribbon and Thorsten Kessler and Rainer Malik and Matthias Prestel and Barbara Stiller and Christine Schofield and Gerard Pasterkamp and Hugh Watkins and Samani, {Nilesh J.} and Timo Wittenberger and Jeanette Erdmann and Heribert Schunkert and Asselbergs, {Folkert W.} and Bj{\"o}rkegren, {Johan L.M.}",

note = "Funding Information: Several figure elements in Fig. 1B (panels II-IV) have been obtained and adapted from Servier Medical Art (www. servier.com) which are distributed under Creative Commons license (https://creativecommons.org/licenses/ by/3.0/). The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007–2013 under grant agreement n° HEALTH-F2-2013-601456 (CVgenes-at-target). Folkert W. Asselbergs is supported by a Dekker scholarship-Junior Staff Member 2014T001 – Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre. Funding Information: Competing Interests: Harri Lempi{\"a}inen is an employee and shareholder of Genedata AG. Johannes Eichner, Claudia Biegert and Timo Wittenberger are employees of Genedata AG. Dr. Bjorkegren and Dr. Michoel are consultants and shareholders in Clinical Gene Networks AB (CGN). Dr. Franzen is part-time employee of CGN. Dr. Bj{\"o}rkegren is also chairman of the board of directors in CGN. TRW and NJS are funded by the British Heart Foundation and SEH and NJS by the UK National Institute for Health Research. Publisher Copyright: {\textcopyright} 2018 The Author(s). Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41598-018-20721-6",

language = "English",

volume = "8",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Lempiäinen, H, Brænne, I, Michoel, T, Tragante, V, Vilne, B, Webb, TR, Kyriakou, T, Eichner, J, Zeng, L, Willenborg, C, Franzen, O, Ruusalepp, A, Goel, A, Van Der Laan, SW, Biegert, C, Hamby, S, Talukdar, HA, Foroughi Asl, H, Dichgans, M, Dreker, T, Graettinger, M, Gribbon, P, Kessler, T, Malik, R, Prestel, M, Stiller, B, Schofield, C, Pasterkamp, G, Watkins, H, Samani, NJ, Wittenberger, T, Erdmann, J, Schunkert, H, Asselbergs, FW & Björkegren, JLM 2018, 'Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets', Scientific Reports, vol. 8, no. 1, 3434. https://doi.org/10.1038/s41598-018-20721-6

TY - JOUR

T1 - Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

AU - Lempiäinen, Harri

AU - Brænne, Ingrid

AU - Michoel, Tom

AU - Tragante, Vinicius

AU - Vilne, Baiba

AU - Webb, Tom R.

AU - Kyriakou, Theodosios

AU - Eichner, Johannes

AU - Zeng, Lingyao

AU - Willenborg, Christina

AU - Franzen, Oscar

AU - Ruusalepp, Arno

AU - Goel, Anuj

AU - Van Der Laan, Sander W.

AU - Biegert, Claudia

AU - Hamby, Stephen

AU - Talukdar, Husain A.

AU - Foroughi Asl, Hassan

AU - Dichgans, Martin

AU - Dreker, Tobias

AU - Graettinger, Mira

AU - Gribbon, Philip

AU - Kessler, Thorsten

AU - Malik, Rainer

AU - Prestel, Matthias

AU - Stiller, Barbara

AU - Schofield, Christine

AU - Pasterkamp, Gerard

AU - Watkins, Hugh

AU - Samani, Nilesh J.

AU - Wittenberger, Timo

AU - Erdmann, Jeanette

AU - Schunkert, Heribert

AU - Asselbergs, Folkert W.

AU - Björkegren, Johan L.M.

N1 - Funding Information: Several figure elements in Fig. 1B (panels II-IV) have been obtained and adapted from Servier Medical Art (www. servier.com) which are distributed under Creative Commons license (https://creativecommons.org/licenses/ by/3.0/). The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007–2013 under grant agreement n° HEALTH-F2-2013-601456 (CVgenes-at-target). Folkert W. Asselbergs is supported by a Dekker scholarship-Junior Staff Member 2014T001 – Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre. Funding Information: Competing Interests: Harri Lempiäinen is an employee and shareholder of Genedata AG. Johannes Eichner, Claudia Biegert and Timo Wittenberger are employees of Genedata AG. Dr. Bjorkegren and Dr. Michoel are consultants and shareholders in Clinical Gene Networks AB (CGN). Dr. Franzen is part-time employee of CGN. Dr. Björkegren is also chairman of the board of directors in CGN. TRW and NJS are funded by the British Heart Foundation and SEH and NJS by the UK National Institute for Health Research. Publisher Copyright: © 2018 The Author(s). Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.

AB - Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.

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U2 - 10.1038/s41598-018-20721-6

DO - 10.1038/s41598-018-20721-6

M3 - Article

C2 - 29467471

AN - SCOPUS:85042360533

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 3434

ER -

Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

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