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Genetic basis of la...
Genetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studies
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- Traylor, Matthew (författare)
- Queen Mary University
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- Persyn, Elodie (författare)
- King's College London
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- Tomppo, Liisa (författare)
- Helsinki University Central Hospital
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- Klasson, Sofia (författare)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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- Abedi, Vida (författare)
- Sigfried and Janet Weis Center for Research
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- Bakker, Mark K. (författare)
- University Medical Center Utrecht
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- Torres, Nuria (författare)
- Hospital de Sant Pau
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- Li, Linxin (författare)
- University of Oxford
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- Bell, Steven (författare)
- University of Cambridge
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- Rutten-Jacobs, Loes (författare)
- F. Hoffmann-La Roche AG
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- Tozer, Daniel J. (författare)
- University of Cambridge
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- Jern, Christina, 1962 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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- Zhang, Yanfei (författare)
- Geisinger Health System
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- Pedersen, Annie, 1981 (författare)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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- Sharma, Pankaj (författare)
- Royal Holloway University of London
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- Jimenez-Conde, Jordi (författare)
- Pompeu Fabra University,Autonomous University of Barcelona
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- Rundek, Tatjana (författare)
- University of Miami
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- Grewal, Raji P. (författare)
- Seton Hall University
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- Lindgren, Arne (författare)
- Lund University,Lunds universitet,Klinisk strokeforskning,Forskargrupper vid Lunds universitet,Clinical Stroke Research Group,Lund University Research Groups,Skåne University Hospital
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- Meschia, James F. (författare)
- Mayo Clinic Florida
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- Salomaa, Veikko (författare)
- Finnish National Institute for Health and Welfare
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- Havulinna, Aki (författare)
- Finnish National Institute for Health and Welfare,Institute for Molecular Medicine Finland (FIMM)
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- Kourkoulis, Christina (författare)
- Massachusetts General Hospital,Broad Institute
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- Crawford, Katherine (författare)
- Massachusetts General Hospital,Broad Institute
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- Marini, Sandro (författare)
- Massachusetts General Hospital,Broad Institute
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- Mitchell, Braxton D. (författare)
- University of Maryland School of Medicine,Baltimore Veterans Administration Medical Center
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- Kittner, Steven J. (författare)
- University of Maryland School of Medicine,Baltimore Veterans Administration Medical Center
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- Rosand, Jonathan (författare)
- Massachusetts General Hospital,Broad Institute
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- Dichgans, Martin (författare)
- Ludwig-Maximilian University of Munich,Munich Cluster for Systems Neurology
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- Jern, Christina (författare)
- University of Gothenburg
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- Strbian, Daniel (författare)
- University of Helsinki,Helsinki University Central Hospital
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- Fernandez-Cadenas, Israel (författare)
- Hospital de Sant Pau,Autonomous University of Barcelona
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- Zand, Ramin (författare)
- Geisinger Health System
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- Ruigrok, Ynte (författare)
- University Medical Center Utrecht
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- Rost, Natalia (författare)
- Massachusetts General Hospital
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- Lemmens, Robin (författare)
- University Hospitals Leuven,Catholic University of Leuven
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- Rothwell, Peter M. (författare)
- University of Oxford
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- Anderson, Christopher D. (författare)
- Broad Institute,Massachusetts General Hospital
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- Wardlaw, Joanna (författare)
- University of Edinburgh
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- Lewis, Cathryn M. (författare)
- King's College London
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- Markus, Hugh S. (författare)
- University of Cambridge
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- 2021
- 2021
- Engelska 11 s.
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Ingår i: The Lancet Neurology. - 1474-4422. ; 20:5, s. 351-361
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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https://gup.ub.gu.se...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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- Av författaren/redakt...
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Traylor, Matthew
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Persyn, Elodie
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Tomppo, Liisa
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Klasson, Sofia
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Abedi, Vida
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Bakker, Mark K.
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visa fler...
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Torres, Nuria
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Li, Linxin
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Bell, Steven
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Rutten-Jacobs, L ...
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Tozer, Daniel J.
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Jern, Christina, ...
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Zhang, Yanfei
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Pedersen, Annie, ...
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Sharma, Pankaj
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Jimenez-Conde, J ...
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Rundek, Tatjana
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Grewal, Raji P.
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Lindgren, Arne
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Meschia, James F ...
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Salomaa, Veikko
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Havulinna, Aki
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Kourkoulis, Chri ...
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Crawford, Kather ...
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Marini, Sandro
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Mitchell, Braxto ...
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Kittner, Steven ...
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Rosand, Jonathan
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Dichgans, Martin
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Jern, Christina
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Strbian, Daniel
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Fernandez-Cadena ...
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Zand, Ramin
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Ruigrok, Ynte
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Rost, Natalia
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Lemmens, Robin
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Rothwell, Peter ...
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Anderson, Christ ...
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Wardlaw, Joanna
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Lewis, Cathryn M ...
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Markus, Hugh S.
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- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Neurologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Medicinsk geneti ...
- Artiklar i publikationen
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The Lancet Neuro ...
- Av lärosätet
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Lunds universitet
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Göteborgs universitet