- Title
- Shared genetic susceptibility to ischemic stroke and coronary artery disease : a genome-wide analysis of common variants
- Creator
- Dichgans, Martin; Malik, Rainer; Ódonnell, Christopher J.; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M.; Hengstenberg, Christian; Seshadri, Sudha; Erdmann, Jeanette; Bis, Joshua C.; Peters, Annette; Boncoraglio, Giorgio B.; König, Inke R.; März, Winfred; Meschia, James F.; Kathiresan, Sekar; Ikram, M. Arfan; McPherson, Ruth; Stefansson, Kari; Sudlow, Cathie; Reilly, Muredach; Thompson, John R.; Sharma, Pankaj; Rosand, Jonathon; Hopewell, Jemma C.; Chambers, John C.; Watkins, Hugh; Rothwell, Peter M.; Roberts, Robert; Markus, Hugh S.; Samani, Nilesh J.; Farrall, Martin; Schunkert, Heribert; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Branxton D.; Assimes, Themistocles L.; Levi, Christopher
- Relation
- NHMRC.569257
- Relation
- Stroke Vol. 45, Issue 1, p. 24-36
- Publisher Link
- http://dx.doi.org/10.1161/STROKEAHA.113.00270710.1161/STROKEAHA.113.002707
- Publisher
- Lippincott Williams & Wilkins
- Resource Type
- journal article
- Date
- 2014
- Description
- 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<5x10-8) 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=1.62x10-7) and ABO (PIS=2.6x10-4), as well as at HDAC9 (PLAS=2.32x10-12), 9p21 (PLAS=3.70x10-6), RAI1-PEMT-RASD1 (PLAS=2.69x10-5), EDNRA (PLAS=7.29x10-4), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9x10-4). Conclusions-Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
- Subject
- coronary artery disease; genetics; meta-analysis; polymorphism; stroke; single nucleotide
- Identifier
- http://hdl.handle.net/1959.13/1307490
- Identifier
- uon:21442
- Identifier
- ISSN:0039-2499
- Language
- eng
- Reviewed
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