TY - JOUR
T1 - Shared genetic susceptibility to ischemic stroke and coronary artery disease: 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 - 2014/1/1
Y1 - 2014/1/1
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.
UR - http://www.scopus.com/inward/record.url?scp=84893659261&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.113.002707
DO - 10.1161/STROKEAHA.113.002707
M3 - Journal articles
AN - SCOPUS:84893659261
SN - 0039-2499
VL - 45
SP - 24
EP - 36
JO - Stroke
JF - Stroke
IS - 1
ER -