Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.
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Authors
Dichgans, MartinMalik, Rainer
König, Inke R
Rosand, Jonathan
Clarke, Robert
Gretarsdottir, Solveig
Thorleifsson, Gudmar
Mitchell, Braxton D
Assimes, Themistocles L
Levi, Christopher
O'Donnell, 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
Issue Date
2014-01
Metadata
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Stroke 2014, 45 (1):24-36Abstract
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.Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide 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.
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)).
Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
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To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Additional Links
http://dx.doi.org/ 10.1161/STROKEAHA.113.002707http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112102/
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openAccessae974a485f413a2113503eed53cd6c53
10.1161/STROKEAHA.113.002707
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