Genetic overlap between diagnostic subtypes of ischemic stroke
Elizabeth G Holliday1, Matthew Traylor1, Rainer Malik1
1From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia; Clinical Research Design, IT and Statistical Support Unit, Public Health Research Program, Hunter Medical Research Institute, Newcastle, Australia (E.G.H., C.O., J.A.); Department of Clinical Neurosciences, University of Cambridge, UK (M.T., S.B., H.S.M.); Institute for Stroke and Dementia Research, Klinikum der Universität Mün-chen, Ludwig-Maximilians-Universität, Munich, Germany (R.M., M.D.); Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA (G.F., J.R.); Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA (G.F., J.R.); Clinical Trial Service Unit and Epidemiological Studies Unit (J.C.H., R.C.) and Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience (P.M.R.), University of Oxford, UK; Department of Medicine (Y.-C.C., B.D.M.) and Department of Neurology (J.W.C., S.J.K.), University of Maryland School of Medicine, Baltimore, MD; Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College, London, UK (I.C.); Cardiovascular Health Research Unit, Department of Medicine (J.C.B., B.M.P., K.L.W.) and Department of Epidemiology (B.M.P.), University of Washington, Seattle, WA; Institute of Molecular Medicine and Human Genetics Center, the University of Texas Health Science Center at Houston, TX (E.B., M.F.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.B., E.A.P.); Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD (J.W.C., S.J.K.); Department of Neurology, Rhode Island Hospital, Providence, RI (K.L.F.); Departments of Epidemiology, Neurology, and Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands (M.A.I.); School of Medicine, University of Adelaide, Australia (J.J.); H
Large artery atherosclerosis (LAA) and small vessel disease (SVD) stroke subtypes share a significant genetic basis. Combining these subtypes in analyses may improve the discovery of genetic risk factors for ischemic stroke.
Area of Science:
- Genetics
- Neurology
- Epidemiology
Background:
- Ischemic stroke heterogeneity complicates gene discovery.
- Analyzing diagnostic subtypes can reduce sample size requirements.
- Understanding shared genetic factors is crucial for effective gene discovery.
Purpose of the Study:
- To assess the shared genetic basis among major ischemic stroke subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD).
- To inform potential cross-subtype analyses for enhanced gene discovery.
- To investigate genetic correlations between LAA, cardioembolism, and SVD.
Main Methods:
- Utilized genome-wide summary data from the Metastroke consortium (12,389 ischemic stroke cases, 62,004 controls).
- Estimated genetic correlations between subtypes using linear mixed models and polygenic profile scores.
- Performed a joint meta-analysis of LAA and SVD phenotypes to identify shared risk alleles.
Main Results:
- High genetic correlation observed between LAA and SVD (rg=0.96, P=9×10⁻⁴).
- Moderate genetic correlation between LAA and cardioembolism, and SVD and cardioembolism.
- Joint meta-analysis identified a strong association near the OPRM1 gene for LAA and SVD.
Conclusions:
- Large artery atherosclerosis and small vessel disease, previously considered distinct, share a substantial genetic component.
- Combined analyses of LAA and SVD can increase statistical power for identifying small-effect risk alleles.
- Findings support integrating LAA and SVD in future genetic studies of ischemic stroke.
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