Shared genetic susceptibility to ischemic stroke and coronary artery disease: A genome-wide analysis of common variants

Martin Dichgans, Rainer Malik, Inke R. König, Jonathan Rosand, Robert Clarke, Solveig Gretarsdottir, Gudmar Thorleifsson, Braxton D. Mitchell, Themistocles L. Assimes, Christopher Levi, Christopher J. Ódonnell, Myriam Fornage, Unnur Thorsteinsdottir, Bruce M. Psaty, Christian Hengstenberg, Sudha Seshadri, Jeanette Erdmann, Joshua C. Bis, Annette Peters, Giorgio B. BoncoraglioWinfried März, James F Meschia, Sekar Kathiresan, M. Arfan Ikram, Ruth McPherson, Kari Stefansson, Cathie Sudlow, Muredach P. Reilly, John R. Thompson, Pankaj Sharma, Jemma C. Hopewell, John C. Chambers, Hugh Watkins, Peter M. Rothwell, Robert Roberts, Hugh S. Markus, Nilesh J. Samani, Martin Farrall, Heribert Schunkert

Research output: Contribution to journalArticle

176 Citations (Scopus)

Abstract

Background and Purpose-Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods-Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genomewide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. Results-Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10-7) and ABO (PIS=2.6×10-4), as well as at HDAC9 (PLAS=2.32×10-12), 9p21 (PLAS=3.70×10-6), RAI1-PEMT-RASD1 (PLAS=2.69×10-5), EDNRA (PLAS=7.29×10-4), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10-4). Conclusions-Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

Original languageEnglish (US)
Pages (from-to)24-36
Number of pages13
JournalStroke
Volume45
Issue number1
DOIs
StatePublished - Jan 2014

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Genetic Predisposition to Disease
Coronary Artery Disease
Stroke
Genome
Arteries
Meta-Analysis
Phenotype
Joints

Keywords

  • Coronary artery disease
  • Genetics
  • Meta-analysis
  • Polymorphism
  • Single nucleotide
  • Stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Dichgans, M., Malik, R., König, I. R., Rosand, J., Clarke, R., Gretarsdottir, S., ... Schunkert, H. (2014). Shared genetic susceptibility to ischemic stroke and coronary artery disease: A genome-wide analysis of common variants. Stroke, 45(1), 24-36. https://doi.org/10.1161/STROKEAHA.113.002707

Shared genetic susceptibility to ischemic stroke and coronary artery disease : A genome-wide analysis of common variants. / Dichgans, Martin; Malik, Rainer; König, Inke R.; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D.; Assimes, Themistocles L.; Levi, Christopher; Ódonnell, Christopher J.; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M.; Hengstenberg, Christian; Seshadri, Sudha; Erdmann, Jeanette; Bis, Joshua C.; Peters, Annette; Boncoraglio, Giorgio B.; März, Winfried; Meschia, James F; Kathiresan, Sekar; Ikram, M. Arfan; McPherson, Ruth; Stefansson, Kari; Sudlow, Cathie; Reilly, Muredach P.; Thompson, John R.; Sharma, Pankaj; Hopewell, Jemma C.; Chambers, John C.; Watkins, Hugh; Rothwell, Peter M.; Roberts, Robert; Markus, Hugh S.; Samani, Nilesh J.; Farrall, Martin; Schunkert, Heribert.

In: Stroke, Vol. 45, No. 1, 01.2014, p. 24-36.

Research output: Contribution to journalArticle

Dichgans, M, Malik, R, König, IR, Rosand, J, Clarke, R, Gretarsdottir, S, Thorleifsson, G, Mitchell, BD, Assimes, TL, Levi, C, Ódonnell, CJ, Fornage, M, Thorsteinsdottir, U, Psaty, BM, Hengstenberg, C, Seshadri, S, Erdmann, J, Bis, JC, Peters, A, Boncoraglio, GB, März, W, Meschia, JF, Kathiresan, S, Ikram, MA, McPherson, R, Stefansson, K, Sudlow, C, Reilly, MP, Thompson, JR, Sharma, P, Hopewell, JC, Chambers, JC, Watkins, H, Rothwell, PM, Roberts, R, Markus, HS, Samani, NJ, Farrall, M & Schunkert, H 2014, 'Shared genetic susceptibility to ischemic stroke and coronary artery disease: A genome-wide analysis of common variants', Stroke, vol. 45, no. 1, pp. 24-36. https://doi.org/10.1161/STROKEAHA.113.002707
Dichgans, Martin ; Malik, Rainer ; König, Inke R. ; Rosand, Jonathan ; Clarke, Robert ; Gretarsdottir, Solveig ; Thorleifsson, Gudmar ; Mitchell, Braxton D. ; Assimes, Themistocles L. ; Levi, Christopher ; Ódonnell, Christopher J. ; Fornage, Myriam ; Thorsteinsdottir, Unnur ; Psaty, Bruce M. ; Hengstenberg, Christian ; Seshadri, Sudha ; Erdmann, Jeanette ; Bis, Joshua C. ; Peters, Annette ; Boncoraglio, Giorgio B. ; März, Winfried ; Meschia, James F ; Kathiresan, Sekar ; Ikram, M. Arfan ; McPherson, Ruth ; Stefansson, Kari ; Sudlow, Cathie ; Reilly, Muredach P. ; Thompson, John R. ; Sharma, Pankaj ; Hopewell, Jemma C. ; Chambers, John C. ; Watkins, Hugh ; Rothwell, Peter M. ; Roberts, Robert ; Markus, Hugh S. ; Samani, Nilesh J. ; Farrall, Martin ; Schunkert, Heribert. / Shared genetic susceptibility to ischemic stroke and coronary artery disease : A genome-wide analysis of common variants. In: Stroke. 2014 ; Vol. 45, No. 1. pp. 24-36.
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abstract = "Background and Purpose-Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods-Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genomewide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. Results-Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10-7) and ABO (PIS=2.6×10-4), as well as at HDAC9 (PLAS=2.32×10-12), 9p21 (PLAS=3.70×10-6), RAI1-PEMT-RASD1 (PLAS=2.69×10-5), EDNRA (PLAS=7.29×10-4), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10-4). Conclusions-Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.",
keywords = "Coronary artery disease, Genetics, Meta-analysis, Polymorphism, Single nucleotide, Stroke",
author = "Martin Dichgans and Rainer Malik and K{\"o}nig, {Inke R.} and Jonathan Rosand and Robert Clarke and Solveig Gretarsdottir and Gudmar Thorleifsson and Mitchell, {Braxton D.} and Assimes, {Themistocles L.} and Christopher Levi and {\'O}donnell, {Christopher J.} and Myriam Fornage and Unnur Thorsteinsdottir and Psaty, {Bruce M.} and Christian Hengstenberg and Sudha Seshadri and Jeanette Erdmann and Bis, {Joshua C.} and Annette Peters and Boncoraglio, {Giorgio B.} and Winfried M{\"a}rz and Meschia, {James F} and Sekar Kathiresan and Ikram, {M. Arfan} and Ruth McPherson and Kari Stefansson and Cathie Sudlow and Reilly, {Muredach P.} and Thompson, {John R.} and Pankaj Sharma and Hopewell, {Jemma C.} and Chambers, {John C.} and Hugh Watkins and Rothwell, {Peter M.} and Robert Roberts and Markus, {Hugh S.} and Samani, {Nilesh J.} and Martin Farrall and Heribert Schunkert",
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TY - JOUR

T1 - Shared genetic susceptibility to ischemic stroke and coronary artery disease

T2 - A genome-wide analysis of common variants

AU - Dichgans, Martin

AU - Malik, Rainer

AU - König, Inke R.

AU - Rosand, Jonathan

AU - Clarke, Robert

AU - Gretarsdottir, Solveig

AU - Thorleifsson, Gudmar

AU - Mitchell, Braxton D.

AU - Assimes, Themistocles L.

AU - Levi, Christopher

AU - Ódonnell, Christopher J.

AU - Fornage, Myriam

AU - Thorsteinsdottir, Unnur

AU - Psaty, Bruce M.

AU - Hengstenberg, Christian

AU - Seshadri, Sudha

AU - Erdmann, Jeanette

AU - Bis, Joshua C.

AU - Peters, Annette

AU - Boncoraglio, Giorgio B.

AU - März, Winfried

AU - Meschia, James F

AU - Kathiresan, Sekar

AU - Ikram, M. Arfan

AU - McPherson, Ruth

AU - Stefansson, Kari

AU - Sudlow, Cathie

AU - Reilly, Muredach P.

AU - Thompson, John R.

AU - Sharma, Pankaj

AU - Hopewell, Jemma C.

AU - Chambers, John C.

AU - Watkins, Hugh

AU - Rothwell, Peter M.

AU - Roberts, Robert

AU - Markus, Hugh S.

AU - Samani, Nilesh J.

AU - Farrall, Martin

AU - Schunkert, Heribert

PY - 2014/1

Y1 - 2014/1

N2 - Background and Purpose-Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods-Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genomewide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. Results-Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10-7) and ABO (PIS=2.6×10-4), as well as at HDAC9 (PLAS=2.32×10-12), 9p21 (PLAS=3.70×10-6), RAI1-PEMT-RASD1 (PLAS=2.69×10-5), EDNRA (PLAS=7.29×10-4), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10-4). Conclusions-Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

AB - Background and Purpose-Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods-Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genomewide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. Results-Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10-7) and ABO (PIS=2.6×10-4), as well as at HDAC9 (PLAS=2.32×10-12), 9p21 (PLAS=3.70×10-6), RAI1-PEMT-RASD1 (PLAS=2.69×10-5), EDNRA (PLAS=7.29×10-4), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10-4). Conclusions-Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

KW - Coronary artery disease

KW - Genetics

KW - Meta-analysis

KW - Polymorphism

KW - Single nucleotide

KW - Stroke

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