Abstract
Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10−8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10−4; discovery and replication combined OR = 1.21, P = 4.7 × 10−8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.
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Acknowledgements
A complete list of funding acknowledgments is included in the Supplementary Note. We are grateful to the participants with ischemic stroke and also to their families for participating in this study. Australian population control data were derived from the Hunter Community Study. We also thank the University of Newcastle for funding and the men and women of the Hunter region who participated in this study. This research was funded by grants from the Australian National Health and Medical Research Council (NHMRC; project grant 569257), the Australian National Heart Foundation (NHF; project grant G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme and the Vincent Fairfax Family Foundation in Australia. E.G.H. is supported by the Australian NHMRC Fellowship scheme. J.G. is supported by a Practitioner Fellowship from the NHMRC and a Senior Clinical Research Fellowship from the Australian Office of Health and Medical Research. The principal funding for the Wellcome Trust Case Control Consortium 2 (WTCCC2) ischemic stroke study was provided by the Wellcome Trust, as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). This work was also supported by the European Community's Sixth Framework Programme (LSHM-CT-2007-037273), the Wellcome Trust core award (090532/Z/09/Z) and AstraZeneca. M. Farrall is a member of the Oxford British Heart Foundation (BHF) Centre of Research Excellence. The Siblings with Ischemic Stroke Study (SWISS) and the Ischemic Stroke Genetics Study (ISGS) were funded by grants from the US National Institute of Neurological Disorders and Stroke. Additional funding was provided by the US National Institute of Neurological Disorders and Stroke (U01NS069208). The Rotterdam Study received principal funding for this report from the Netherlands Heart Foundation (grant 2009B102).
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S.A.K., J.W.S., L.F.L., P.M., R.J.S., C.L. and J.A. designed the study. E.G.H. performed statistical analyses in the discovery cohort, meta-analyses of replication data and wrote the first draft of the manuscript. T.-J.E. and R.J.S. coordinated genotyping of the discovery cohort. J.M.M., J.G., J.J., G.J.H., R.B., M.W.P., J.W.S., L.F.L., C.L., M.M., R.P., W.S. and J.A. performed phenotype collection and data management in the Australian sample. E. Biros, M.D.L. and C.O. performed bioinformatic analyses. Replication data were provided by S. Barlera, S. Bevan, J.C.B., E. Boerwinkle, G.B.B., T.G.B., R.D.B., Y.-C.C., J.W.C., I.C., W.J.D., M. Fornage, K.L.F., S.G., A.G., M.A.I., W.T.L., R.M., J.F.M., B.D.M., T.H.M., M.A.N., E.A.P., B.M.P., P.S., K.S., G.T., M.T., U.T., B.F.J.V., K.L.W., B.B.W., C.S., P.M.R., M. Farrall, M.D., J.R. and H.S.M. All authors critically reviewed the manuscript and gave advice on the contents of the paper.
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A full list of members is provided in the Supplementary Note.
A full list of members is provided in the Supplementary Note.
A full list of members is provided in the Supplementary Note.
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Supplementary Tables 1–12, Supplementary Figures 1–7 and Supplementary Note (PDF 1137 kb)
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Holliday, E., Maguire, J., Evans, TJ. et al. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nat Genet 44, 1147–1151 (2012). https://doi.org/10.1038/ng.2397
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DOI: https://doi.org/10.1038/ng.2397
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