Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke

Dorothea Pfeiffer¹, Bowang Chen², Kristina Schlicht³, Philip Ginsbach⁴, Sherine Abboud⁵, Anna Bersano⁶, Steve Bevan⁷, Tobias Brandt^{1

8}, Valeria Caso⁹, Stéphanie Debette^{10

11}, Philipp Erhart¹², Sandra Freitag-Wolf³, Giacomo Giacalone¹³, Armin J Grau¹⁴, Eyad Hayani¹, Christina Jern^{15

16}, Jordi Jiménez-Conde¹⁷, Manja Kloss¹, Michael Krawczak³, Jin-Moo Lee¹⁸, Robin Lemmens^{19

20

21}, Didier Leys²², Christoph Lichy²³, Jane M Maguire^{24

25}, Juan J Martin²⁶, Antti J Metso²⁷, Tiina M Metso²⁷, Braxton D Mitchell^{28

29}, Alessandro Pezzini³⁰, Jonathan Rosand³¹, Natalia S Rost³², Martin Stenman^{33

34}, Turgut Tatlisumak^{27

35

36}, Vincent Thijs^{37

38}, Emmanuel Touzé^{39

40}, Christopher Traenka⁴¹, Inge Werner¹, Daniel Woo⁴², Elisabetta Del Zotto³⁰, Stefan T Engelter^{41

43

44}, Steven J Kittner⁴⁵, John W Cole⁴⁵, Caspar Grond-Ginsbach¹, Philippe A Lyrer⁴¹, Arne Lindgren^{33

34}; CADISP; GISCOME; SiGN studies; and ISGC

Affiliations

¹ From the Department of Neurology, Heidelberg University Hospital, Germany (D.P., T.B., E.H., M. Kloss, I.W., C.G.-G.).
² Department of Biology, Southern University of Science and Technology, Shenzhen, China (B.C.).
³ Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein Campus Kiel, Germany (K.S., S.F.-W., M. Krawczak).
⁴ School of Informatics, University of Edinburgh, United Kingdom (P.G.).
⁵ Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium (S.A.).
⁶ Cerebrovascular Unit IRCCS Foundation C. Besta Neurological Institute, Milan, Italy (A.B.).
⁷ School of Life Science, University of Lincoln, United Kingdom (S.B.).
⁸ Suva/Swiss National Accident Insurance Fund, Lucerne, Switzerland (T.B.).
⁹ Stroke Unit, Perugia University Hospital, Italy (V.C.).
¹⁰ Inserm, Bordeaux Population Health Research Center, UMR 1219, University of Bordeaux, France (S.D.).
¹¹ Department of Neurology, Bordeaux University Hospital, France (S.D.).
¹² Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Germany (P.E.).
¹³ Department of Neurology, San Raffaele University Hospital, Milan, Italy (G.G.).
¹⁴ Department of Neurology, Klinikum Ludwigshafen, Germany (A.J.G.).
¹⁵ The Sahlgrenska Academy, University of Gothenburg, Sweden (C.J.).
¹⁶ Sahlgrenska University Hospital, Sweden (C.J.).
¹⁷ IMIM-Parc de Salut Mar, Universitat Autonoma de Barcelona, Spain (J.J.-C.).
¹⁸ Department of Neurology, Washington University School of Medicine, St Louis, MO (J.-M.L.).
¹⁹ Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, KU Leuven, University of Leuven, Belgium (R.L.).
²⁰ VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium (R.L.).
²¹ Department of Neurology, University Hospitals Leuven, Belgium (R.L.).
²² Department of Neurology, University of Lille, France (D.L.).
²³ Department of Neurology, Klinikum Memmingen, Germany (C.L.).
²⁴ Faculty of Health, University of Technology Sydney, Australia (J.M.M.).
²⁵ Hunter Medical Research Institute, Priority Research Centre for Stroke and Traumatic Brain Injury, University of Newcastle, Australia (J.M.M.).
²⁶ Department of Neurology, Sanatorio Allende, Cordoba, Argentina (J.J.M.).
²⁷ Department of Neurology, Helsinki University Central Hospital, Finland (A.J.M., T.M.M., T.T.).
²⁸ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (B.D.M.).
²⁹ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD (B.D.M.).
³⁰ Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Italy (A.P., E.D.Z.).
³¹ Center for Genomic Medicine (J.R.), Massachusetts General Hospital, Boston.
³² Department of Neurology (N.S.R.), Massachusetts General Hospital, Boston.
³³ Department of Clinical Sciences Lund, Neurology, Lund University, Sweden (M.S., A.L.).
³⁴ Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (M.S., A.L.).
³⁵ Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden (T.T.).
³⁶ Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden (T.T.).
³⁷ Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia (V.T.).
³⁸ Department of Neurology, Austin Health, Heidelberg, Victoria, Australia (V.T.).
³⁹ Paris Descartes University, INSERM UMR S894, Department of Neurology, Sainte-Anne Hospital, Paris, France (E.T.).
⁴⁰ Normandie Université, Université Caen-Normandie, Inserm U1237, CHU Côte de Nacre, Service de Neurologie, Caen, France (E.T.).
⁴¹ Department of Neurology and Stroke Center, University Hospital Basel, Switzerland (C.T., S.T.E., P.A.L.).
⁴² Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (D.W.).
⁴³ Neurorehabilitation Unit, University of Basel, Switzerland (S.T.E.).
⁴⁴ University Center for Medicine of Aging, Felix Platter Hospital, Basel, Switzerland (S.T.E.).
⁴⁵ Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD (S.J.K., J.W.C.); and Department of Neurology University of Maryland School of Medicine, Baltimore (S.J.K., J.W.C.).

PMID: 30661490
PMCID: PMC7441497
DOI: 10.1161/STROKEAHA.118.021856

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke

Dorothea Pfeiffer et al. Stroke. 2019 Feb.

. 2019 Feb;50(2):298-304.

doi: 10.1161/STROKEAHA.118.021856.

Authors

Affiliations

¹ From the Department of Neurology, Heidelberg University Hospital, Germany (D.P., T.B., E.H., M. Kloss, I.W., C.G.-G.).
² Department of Biology, Southern University of Science and Technology, Shenzhen, China (B.C.).
³ Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein Campus Kiel, Germany (K.S., S.F.-W., M. Krawczak).
⁴ School of Informatics, University of Edinburgh, United Kingdom (P.G.).
⁵ Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium (S.A.).
⁶ Cerebrovascular Unit IRCCS Foundation C. Besta Neurological Institute, Milan, Italy (A.B.).
⁷ School of Life Science, University of Lincoln, United Kingdom (S.B.).
⁸ Suva/Swiss National Accident Insurance Fund, Lucerne, Switzerland (T.B.).
⁹ Stroke Unit, Perugia University Hospital, Italy (V.C.).
¹⁰ Inserm, Bordeaux Population Health Research Center, UMR 1219, University of Bordeaux, France (S.D.).
¹¹ Department of Neurology, Bordeaux University Hospital, France (S.D.).
¹² Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Germany (P.E.).
¹³ Department of Neurology, San Raffaele University Hospital, Milan, Italy (G.G.).
¹⁴ Department of Neurology, Klinikum Ludwigshafen, Germany (A.J.G.).
¹⁵ The Sahlgrenska Academy, University of Gothenburg, Sweden (C.J.).
¹⁶ Sahlgrenska University Hospital, Sweden (C.J.).
¹⁷ IMIM-Parc de Salut Mar, Universitat Autonoma de Barcelona, Spain (J.J.-C.).
¹⁸ Department of Neurology, Washington University School of Medicine, St Louis, MO (J.-M.L.).
¹⁹ Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, KU Leuven, University of Leuven, Belgium (R.L.).
²⁰ VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium (R.L.).
²¹ Department of Neurology, University Hospitals Leuven, Belgium (R.L.).
²² Department of Neurology, University of Lille, France (D.L.).
²³ Department of Neurology, Klinikum Memmingen, Germany (C.L.).
²⁴ Faculty of Health, University of Technology Sydney, Australia (J.M.M.).
²⁵ Hunter Medical Research Institute, Priority Research Centre for Stroke and Traumatic Brain Injury, University of Newcastle, Australia (J.M.M.).
²⁶ Department of Neurology, Sanatorio Allende, Cordoba, Argentina (J.J.M.).
²⁷ Department of Neurology, Helsinki University Central Hospital, Finland (A.J.M., T.M.M., T.T.).
²⁸ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (B.D.M.).
²⁹ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD (B.D.M.).
³⁰ Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Italy (A.P., E.D.Z.).
³¹ Center for Genomic Medicine (J.R.), Massachusetts General Hospital, Boston.
³² Department of Neurology (N.S.R.), Massachusetts General Hospital, Boston.
³³ Department of Clinical Sciences Lund, Neurology, Lund University, Sweden (M.S., A.L.).
³⁴ Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (M.S., A.L.).
³⁵ Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden (T.T.).
³⁶ Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden (T.T.).
³⁷ Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia (V.T.).
³⁸ Department of Neurology, Austin Health, Heidelberg, Victoria, Australia (V.T.).
³⁹ Paris Descartes University, INSERM UMR S894, Department of Neurology, Sainte-Anne Hospital, Paris, France (E.T.).
⁴⁰ Normandie Université, Université Caen-Normandie, Inserm U1237, CHU Côte de Nacre, Service de Neurologie, Caen, France (E.T.).
⁴¹ Department of Neurology and Stroke Center, University Hospital Basel, Switzerland (C.T., S.T.E., P.A.L.).
⁴² Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (D.W.).
⁴³ Neurorehabilitation Unit, University of Basel, Switzerland (S.T.E.).
⁴⁴ University Center for Medicine of Aging, Felix Platter Hospital, Basel, Switzerland (S.T.E.).
⁴⁵ Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD (S.J.K., J.W.C.); and Department of Neurology University of Maryland School of Medicine, Baltimore (S.J.K., J.W.C.).

PMID: 30661490
PMCID: PMC7441497
DOI: 10.1161/STROKEAHA.118.021856

Abstract

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Keywords: DNA copy number variations; genetics; polymorphism, single nucleotide; prognosis; stroke.

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Conflict of interest statement

Disclosures

Dr Lindgren reports speech and seminar honoraria from Bayer and BMS/Pfizer and consulting for Bayer, AstraZeneca, Boehringer Ingelheim, BMS/Pfizer and Reneuron. The other authors report no conflicts.

In part presented at the International Stroke Genetics Consortium Workshop, April 12, 2018, Kyoto, Japan.

Figures

**Figure 1.. Odds ratios (OR) for favorable outcome after stroke for different types of genetic imbalance.**
The association between outcome and different types of genetic imbalance was assessed by logistic regression analysis, adjusted for age, sex and the first 10 ancestry-derived principal components as potential confounders, and including stroke etiology and stroke severity (NIH stroke scale) as additional covariates.

See this image and copyright information in PMC

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Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke

Affiliations

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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