Web of Science: 75 citas, Scopus: 76 citas, Google Scholar: citas,
Genetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studies
Traylor, Matthew (Clinical Pharmacology and The Barts Heart Centre and NIHR Barts Biomedical Research Centre, Barts Health NHS Trust, William Harvey Research Institute, Queen Mary University of London, London, UK)
Persyn, Elodie (King's College London)
Tomppo, Liisa (Helsinki University Hospital (Finlàndia))
Klasson, Sofia (Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden)
Abedi, Vida (Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Health System, Danville, PA, USA)
Bakker, Mark K. (Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands)
Torres, Nuria (Institut d'Investigació Biomèdica Sant Pau)
Li, Linxin (University of Oxford. Nuffield Department of Clinical Neuroscience)
Bell, Steven (Unversity of Cambridge)
Rutten-Jacobs, Loes (Product Development Personalized Health Care, F Hoffmann-La Roche, Basel, Switzerland)
Tozer, Daniel J. (Clinical Neurosciences, University of Cambridge, Cambridge, UK)
Griessenauer, Christoph J. (Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria)
Zhang, Yanfei (Genomic Medicine Institute, Geisinger Health System, Danville, PA, USA)
Pedersen, Annie (Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden)
Sharma, Pankaj (Institute of Cardiovascular Research, Royal Holloway University of London, London, UK)
Jimenez-Conde, Jordi (Institut Hospital del Mar d'Investigacions Mèdiques)
Rundek, Tatjana (University of Miami. Miller School of Medicine)
Grewal, Raji P. (Neuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, South Orange, NJ, USA)
Lindgren, Arne (Lund University (Lund, Suècia))
Meschia, James F. (Mayo Clinic (Jacksonville, Estats Units d'Amèrica))
Salomaa, Veikko (Finnish Institute for Health and Welfare (Helsinki, Finlàndia))
Havulinna, Aki S (Institute for Molecular Medicine Finland (FIMM HiLIFE), Helsinki, Finland)
Kourkoulis, Christina (Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Crawford, Katherine (Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Marini, Sandro (Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Mitchell, Braxton D. (Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA)
Kittner, Steven J. (Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA)
Rosand, Jonathan (Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Dichgans, Martin (Munich Cluster for Systems Neurology (SyNergy), Munich, Germany)
Jern, Christina (Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden)
Strbian, Daniel (Helsinki University Hospital (Finlàndia))
Fernandez-Cadenas, Israel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Zand, Ramin (Neuroscience Institute, Geisinger Health System, Danville, PA, USA)
Ruigrok, Ynte (Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands)
Rost, Natalia (Massachusetts General Hospital (Boston))
Lemmens, Robin (University Hospitals Leuven (Bèlgica))
Rothwell, Peter M. (University of Oxford. Nuffield Department of Clinical Neuroscience)
Anderson, Christopher D. (Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Wardlaw, Joanna (Centre for Clinical Brain Sciences, UK Dementia Research Institute and Row Fogo Centre for Research into the Ageing Brain, University of Edinburgh, Edinburgh, UK)
Lewis, Cathryn M. (King's College London. Social, Genetic, and Developmental Psychiatry Centre)
Markus, Hugh S. (Clinical Neurosciences, University of Cambridge, Cambridge, UK)
Universitat Autònoma de Barcelona

Fecha: 2021
Resumen: 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. 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. 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. 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. British Heart Foundation.
Derechos: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Lengua: Anglès
Documento: Article ; altres ; Versió publicada
Publicado en: The Lancet neurology, Vol. 20 (may 2021) , p. 351-361, ISSN 1474-4465

DOI: 10.1016/S1474-4422(21)00031-4
PMID: 33773637


11 p, 1.9 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
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 Registro creado el 2021-05-10, última modificación el 2024-01-07



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