Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies
Year: 2021
Type: review
Study design: Observational Study
Abstract: BACKGROUND: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. METHODS: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. FINDINGS: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. INTERPRETATION: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. FUNDING: British Heart Foundation.
Source: The Lancet Neurology
Authors: Matthew Traylor, Elodie Persyn, Liisa Tomppo, Sofia Klasson, Vida Abedi, Mark K Bakker, Nuria Torres, Linxin Li, Steven Bell, Loes Rutten-Jacobs, Daniel J Tozer, Christoph J Griessenauer, Yanfei Zhang, Annie Pedersen, Pankaj Sharma, Jordi Jimenez-Conde, Tatjana Rundek, Raji P Grewal, Arne Lindgren, James F Meschia, Veikko Salomaa, Aki Havulinna, Christina Kourkoulis, Katherine Crawford, Sandro Marini, Braxton D Mitchell, Steven J Kittner, Jonathan Rosand, Martin Dichgans, Christina Jern, Daniel Strbian, Israel Fernandez-Cadenas, Ramin Zand, Ynte Ruigrok, Natalia Rost, Robin Lemmens, Peter M Rothwell, Christopher D Anderson, Joanna Wardlaw, Cathryn M Lewis, Hugh S Markus
Institutions: Queen Mary University of London, Barts Health NHS Trust, National Institute for Health and Care Research, William Harvey Research Institute, King's College London, Helsinki University Hospital, University of Gothenburg, Geisinger Health System, University Medical Center Utrecht, Hospital de Sant Pau, Institut de Recerca Sant Pau, University of Oxford, University of Cambridge, F. Hoffmann-La Roche AG, Paracelsus Medical University, Geisinger Neuroscience Institute, Royal Holloway University of London, Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Hospital Del Mar, Municipal Institute for Medical Research, Hospital del Mar Research Institute, University of Miami, Seton Hall University, Lund University, Skåne University Hospital, Mayo Clinic in Florida, Finnish Institute for Health and Welfare, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, Broad Institute, Harvard University, Massachusetts General Hospital, Massachusetts Institute of Technology, University of Maryland, Baltimore, Baltimore VA Medical Center, Munich Cluster for Systems Neurology, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, University of Helsinki, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, UK Dementia Research Institute, University of Edinburgh
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: U.S. Department of Veterans Affairs, Regeneron Pharmaceuticals, University of Essex, Wellcome Trust, Understanding Society, Barts Charity, National Institute for Health and Care Research, British Heart Foundation, Stroke Association, King's College London, Fonds Wetenschappelijk Onderzoek, Hjärt-Lungfonden, Vetenskapsrådet, Vlaamse regering, National Institutes of Health, Manchester Biomedical Research Centre, Medical Research Council, Economic and Social Research Council, Sahlgrenska Akademin, NIHR Oxford Biomedical Research Centre, NIHR Barts Biomedical Research Centre, Queen Mary University of London, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: WTCCC2 core activities., NIHR Senior Investigator Award, WTCCC2 core activities, G2469409990, G302422484, G3440585208, G4030358845, G4594809122, G482433192, On the Hemostatic and Inflammatory Pathways in Stroke, G5252260388, G5615305647, G5714867875, G573982542, Using genetics to understand why disease of the small blood vessels in the brain occurs, G6047438729, G6144943374, CNV And Stroke (CaNVAS), G6804723138, Mid-Atlantic Nutrition Obesity Research Center, WTCCC2 core activities., G712881263, Using genetics to explore the pathophysiology of cerebral small vessel disease. 15, G7650407507, The NINDS International Stroke Genetics Consortium Study, G8788107066, G9000040700, G9000072696, G9000120590, G9000261712
OpenAlex ID: W3136867187