04329nas a2200781 4500008004100000022001400041245012500055210006900180260001300249300001000262490000700272520197700279653001902256653002802275653003702303653003802340653003402378653001102412653001402423653003602437653003102473653001702504653001102521100002102532700001802553700002002571700002102591700001902612700002702631700002502658700002502683700002902708700002202737700003002759700002002789700002802809700002002837700002802857700002002885700002202905700001902927700002002946700002802966700002002994700002203014700002203036700002003058700002003078700002103098700001903119700002403138700002203162700001903184700002303203700002203226700001803248700002303266700002003289700002003309700002203329700002003351700002403371710002603395710002603421710001903447710004503466856003603511 2014 eng d a1524-462800aShared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.0 aShared genetic susceptibility to ischemic stroke and coronary ar c2014 Jan a24-360 v453 a
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 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.
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.
10aBrain Ischemia10aCoronary Artery Disease10aData Interpretation, Statistical10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPhenotype10aPolymorphism, Single Nucleotide10aReproducibility of Results10aRisk Factors10aStroke1 aDichgans, Martin1 aMalik, Rainer1 aKönig, Inke, R1 aRosand, Jonathan1 aClarke, Robert1 aGretarsdottir, Solveig1 aThorleifsson, Gudmar1 aMitchell, Braxton, D1 aAssimes, Themistocles, L1 aLevi, Christopher1 aO'Donnell, Christopher, J1 aFornage, Myriam1 aThorsteinsdottir, Unnur1 aPsaty, Bruce, M1 aHengstenberg, Christian1 aSeshadri, Sudha1 aErdmann, Jeanette1 aBis, Joshua, C1 aPeters, Annette1 aBoncoraglio, Giorgio, B1 aMärz, Winfried1 aMeschia, James, F1 aKathiresan, Sekar1 aIkram, Arfan, M1 aMcPherson, Ruth1 aStefansson, Kari1 aSudlow, Cathie1 aReilly, Muredach, P1 aThompson, John, R1 aSharma, Pankaj1 aHopewell, Jemma, C1 aChambers, John, C1 aWatkins, Hugh1 aRothwell, Peter, M1 aRoberts, Robert1 aMarkus, Hugh, S1 aSamani, Nilesh, J1 aFarrall, Martin1 aSchunkert, Heribert1 aMETASTROKE Consortium1 aCARDIoGRAM consortium1 aC4D Consortium1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/6370