Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls-Reference-Cited by-同舟云学术

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

Published:2019-07 Issue:7 Volume:12 Page:
ISSN:2574-8300
Container-title:Circulation: Genomic and Precision Medicine
language:en
Short-container-title:Circ: Genomic and Precision Medicine

Author:

Traylor Matthew¹²,Anderson Christopher D.³⁴⁵⁶,Rutten-Jacobs Loes C.A.⁷,Falcone Guido J.⁸,Comeau Mary E.⁹,Ay Hakan¹⁰¹¹,Sudlow Cathie L.M.¹²¹³,Xu Huichun¹⁴,Mitchell Braxton D.¹⁴¹⁵,Cole John W.¹⁶¹⁷,Rexrode Kathryn¹⁸,Jimenez-Conde Jordi¹⁹²⁰,Schmidt Reinhold²¹,Grewal Raji P.²²,Sacco Ralph²³,Ribases Marta²⁴²⁵²⁶,Rundek Tatjana²³,Rosand Jonathan³⁴⁵⁶,Dichgans Martin²⁷²⁸,Lee Jin-Moo²⁹,Langefeld Carl D.⁹,Kittner Steven J.¹⁶¹⁷,Markus Hugh S.¹,Woo Daniel³⁰,Malik Rainer²⁷,

Affiliation:

1. Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge (M.T., H.S.M.).

2. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (M.T.).

3. Center for Genomic Medicine (C.D.A., J.R.), Massachusetts General Hospital, Boston.

4. J. Philip Kistler Stroke Research Center, Department of Neurology (C.D.A., J.R.), Massachusetts General Hospital, Boston.

5. Division of Neurocritical Care and Emergency Neurology, Department of Neurology (C.D.A., J.R.), Massachusetts General Hospital, Boston.

6. Program in Medical and Population Genetics, Broad Inst, Cambridge, MA (C.D.A., J.R.).

7. German Center for Neurodegenerative Diseases, Population Health Sciences, Bonn, Germany (L.C.A.R.-J.).

8. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT (G.J.F.).

9. Department of Biostatistical Sciences, Division of Public Health Sciences, School of Medicine, Wake Forest University, Winston-Salem, NC (M.E.C., C.D.L.).

10. Stroke Service (H.A.), Massachusetts General Hospital, Boston.

11. A.A. Martinos Center for Biomedical Imaging, Department of Radiology (H.A.), Massachusetts General Hospital, Boston.

12. Center for Clinical Brain Sciences, University of Edinburgh (C.L.M.S.).

13. Usher Institute of Population Health Sciences and Informatics, Nine Bioquarter, Edinburgh, United Kingdom (C.L.M.S.).

14. Division of Endocrinology, Diabetes and Nutrition, Department of Medicine (H.X., B.D.M.,), University of Maryland School of Medicine.

15. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center (B.D.M.).

16. Department of Neurology (S.J.K., J.W.C), University of Maryland School of Medicine.

17. Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD (J.W.C., S.J.K).

18. Channing Division of Network Medicine and Division of Women’s Health, Department of Medicine, Brigham and Women’s Hospital, Boston, MA (K.R.).

19. Neurovascular Research Unit, Department of Neurology (J.J.-C.), Institut Municipal d’Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain.

20. Program in Inflammation and Cardiovascular Disorders (J.J.-C.), Institut Municipal d’Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain.

21. Department of Neurology, Medical University of Graz, Austria (R. Schmidt).

22. Neuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, South Orange, NJ (R.P.G.).

23. Department of Neurology, Miller School of Medicine, University of Miami, FL (R. Sacco, T.R.).

24. Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (M.R.).

25. Department of Psychiatry, Hospital Universitari Vall d’Hebron (M.R.).

26. Biomedical Network Research Center on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain (M.R.).

27. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München (M.D., R.M.).

28. Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.).

29. Department of Neurology, Radiology, and Biomedical Engineering, Washington University School of Medicine, St Louis, MO (J.-M.L.).

30. Department of Neurology and Rehabilitation Medicine and Comprehensive Stroke Center, University of Cincinnati, OH (D.W.).

Abstract

Background: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. Methods: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. Results: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. Conclusions: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

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