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Title: Genetic variation at 16q24.2 is associated with small vessel stroke
Austin Authors: Traylor, Matthew;Malik, Rainer;Nalls, Mike A;Cotlarciuc, Ioana;Radmanesh, Farid;Thorleifsson, Gudmar;Hanscombe, Ken B;Langefeld, Carl;Saleheen, Danish;Rost, Natalia S;Yet, Idil;Spector, Tim D;Bell, Jordana T;Hannon, Eilis;Mill, Jonathan;Chauhan, Ganesh;Debette, Stephanie;Bis, Joshua C;Longstreth, WT Jr;Ikram, M Arfan;Launer, Lenore J;Seshadri, Sudha;Hamilton-Bruce, Monica Anne;Jimenez-Conde, Jordi;Cole, John W;Schmidt, Reinhold;Słowik, Agnieszka;Lemmens, Robin;Lindgren, Arne;Melander, Olle;Grewal, Raji P;Sacco, Ralph L;Rundek, Tatjana;Rexrode, Kathryn;Arnett, Donna K;Johnson, Julie A;Benavente, Oscar R;Wasssertheil-Smoller, Sylvia;Lee, Jin-Moo;Pulit, Sara L;Wong, Quenna;Rich, Stephen S;de Bakker, Paul IW;McArdle, Patrick F;Woo, Daniel;Anderson, Christopher D;Xu, Huichun;Heitsch, Laura;Fornage, Myriam;Jern, Christina;Stefansson, Kari;Thorsteinsdottir, Unnur;Gretarsdottir, Solveig;Lewis, Cathryn M;Sharma, Pankaj;Sudlow, Cathie LM;Rothwell, Peter M;Boncoraglio, Giorgio B;Thijs, Vincent;Levi, Chris;Meschia, James F;Rosand, Jonathan;Kittner, Steven J;Mitchell, Braxton D;Dichgans, Martin;Worrall, Bradford B;Markus, Hugh S
Institutional Author: METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium
International Stroke Genetics Consortium
Affiliation: Austin Health, Heidelberg, Victoria, Australia
Department of Medical and Molecular Genetics, King's College London, London, UK
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
Institute of Cardiovascular Research Royal Holloway University of London, UK
Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA, USA
J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
deCODE genetics/AMGEN, Reykjavik, Iceland
Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, PA, USA
Department of Twin Research & Genetic Epidemiology, King's College London, London, UK
University of Exeter Medical School, University of Exeter, Exeter, UK
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Inserm Research Center for Epidemiology and Biostatistics (U897) - Team Neuroepidemiology, Bordeaux, France
University of Bordeaux, Bordeaux, France
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
Departments of Neurology and Epidemiology, University of Washington, Seattle, WA, USA
Department of Neurology, Epidemiology and Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA
Boston University School of Medicine, Boston, MA, USA
Framingham Heart Study, Framingham, MA, USA
Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Neurovascular Research Group (NEUVAS). Neurology Department., Institut Hospital del Mar d'Investigació Mèdica, Barcelona, Spain
Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, MD, USA
Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Austria
Department of Neurology, Jagiellonian University, Krakow, Poland
KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium
VIB, Vesalius Research Center, Laboratory of Neurobiology, Department of Neurology, Leuven, Belgium
University Hospitals Leuven, Department of Neurology, Leuven, Belgium
Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden
Department of Clinical Sciences, Lund University, Malmö, Sweden
Neuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, South Orange, New Jersey, USA
Department of Neurology, Miller School of Medicine, University of Miami, USA
Harvard Medical School, Boston, USA Center for Faculty Development and Diversity, Brigham and Women's Hospital, Boston, MA, USA
College of Public Health, University of Kentucky, Lexington, KY, USA
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, College of Pharmacy, Gainesville, FL, USA
Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, NY, USA
Stroke Center, Department of Neurology, Washington University School of Medicine, WA, USA
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
Department of Biostatistics, University of Washington, WA, USA
Center for Public Health Genomics, University of Virginia School of Medicine, VA, USA
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Medicine, University of Maryland School of Medicine, MD, USA
University of Cincinnati College of Medicine, Cincinnati, OH, USA
Program in Medical and Population Genetics, Broad Institute, Boston, MA, USA
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
Division of Emergency Medicine, Washington University School of Medicine, St Louis, MO, USA
The University of Texas Health Science Center at Houston, Houston, TX, USA
Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden
Faculty of Medicine, University of Iceland, Reykjavik, Iceland
Center for Clinical Brain Sciences & Institute of Genetics and Molecular Medicine, University of Edinburgh, UK
Nuffield Department of Clinical Neurosciences, University of Oxford, UK
Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy
Department of Neurology, Austin Health, Heidelberg, Victoria, Australia
Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia
John Hunter Hospital, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia
Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA
Munich Cluster of Systems Neurology, SyNergy, Munich, Germany
Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA
troke Research Group, Division of Clinical Neurosciences, University of Cambridge, UK
Issue Date: Mar-2017 2016-12-20
Publication information: Annals of Neurology 2016; 81(3): 383-394
Abstract: OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises a quarter of all ischaemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown younger onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger onset SVS population, to identify novel associations with stroke. METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on mRNA expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (OR(95% CI)=1.16(1.10-1.22); p=3.2x10-9 ). The lead SNP (rs12445022) was also associated with cerebral white matter hyperintensities (OR(95% CI)=1.10(1.05-1.16); p=5.3x10-5 ; N=3,670), but not intracerebral haemorrhage (OR(95% CI)=0.97(0.84-1.12); p=0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p=9.4x10-7 ), and DNA methylation at probe cg16596957 in whole blood (p=5.3x10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements.
DOI: 10.1002/ana.24840
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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