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dc.contributor.authorHelsinki Stroke, Study Dutch Parelsnoer Institute-Cerebrovascular Accident (CVA) Study Group
dc.contributor.authorNational Institute of Neurological Disorders and Stroke (NINDS)
dc.contributor.authorStroke Genetics Network
dc.contributor.authorUK DNA Lacunar Stroke Study Investigators
dc.contributor.authorInternational Stroke Genetics Consortium
dc.contributor.authorTraylor, Matthew
dc.contributor.authorPersyn, Elodie
dc.contributor.authorTomppo, Liisa
dc.contributor.authorKlasson, Sofia
dc.contributor.authorAbedi, Vida
dc.contributor.authorBakker, Mark K
dc.contributor.authorTorres, Nuria
dc.contributor.authorLi, Linxin
dc.contributor.authorBell, Steven
dc.contributor.authorRutten-Jacobs, Loes
dc.contributor.authorTozer, Daniel J
dc.contributor.authorGriessenauer, Christoph J
dc.contributor.authorZhang, Yanfei
dc.contributor.authorPedersen, Annie
dc.contributor.authorSharma, Pankaj
dc.contributor.authorJimenez-Conde, Jordi
dc.contributor.authorRundek, Tatjana
dc.contributor.authorGrewal, Raji P
dc.contributor.authorLindgren, Arne
dc.contributor.authorMeschia, James F
dc.contributor.authorSalomaa, Veikko
dc.contributor.authorHavulinna, Aki
dc.contributor.authorKourkoulis, Christina
dc.contributor.authorCrawford, Katherine
dc.contributor.authorMarini, Sandro
dc.contributor.authorMitchell, Braxton D
dc.contributor.authorKittner, Steven J
dc.contributor.authorRosand, Jonathan
dc.contributor.authorDichgans, Martin
dc.contributor.authorJern, Christina
dc.contributor.authorStrbian, Daniel
dc.contributor.authorFernandez-Cadenas, Israel
dc.contributor.authorZand, Ramin
dc.contributor.authorRuigrok, Ynte
dc.contributor.authorRost, Natalia
dc.contributor.authorLemmens, Robin
dc.contributor.authorRothwell, Peter M
dc.contributor.authorAnderson, Christopher D
dc.contributor.authorWardlaw, Joanna
dc.contributor.authorLewis, Cathryn M
dc.contributor.authorMarkus, Hugh S
dc.date.accessioned2021-07-29T15:30:08Z
dc.date.available2021-07-29T15:30:08Z
dc.date.issued2021-05-01
dc.identifier.citationHelsinki Stroke, Study Dutch Parelsnoer Institute-Cerebrovascular Accident (CVA) Study Group , National Institute of Neurological Disorders and Stroke (NINDS) , Stroke Genetics Network , UK DNA Lacunar Stroke Study Investigators , International Stroke Genetics Consortium , Traylor , M , Persyn , E , Tomppo , L , Klasson , S , Abedi , V , Bakker , M K , Torres , N , Li , L , Bell , S , Rutten-Jacobs , L , Tozer , D J , Griessenauer , C J , Zhang , Y , Pedersen , A , Sharma , P , Jimenez-Conde , J , Rundek , T , Grewal , R P , Lindgren , A , Meschia , J F , Salomaa , V , Havulinna , A , Kourkoulis , C , Crawford , K , Marini , S , Mitchell , B D , Kittner , S J , Rosand , J , Dichgans , M , Jern , C , Strbian , D , Fernandez-Cadenas , I , Zand , R , Ruigrok , Y , Rost , N , Lemmens , R , Rothwell , P M , Anderson , C D , Wardlaw , J , Lewis , C M & Markus , H S 2021 , ' Genetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studies ' , Lancet Neurology , vol. 20 , no. 5 , pp. 351-361 . https://doi.org/10.1016/S1474-4422(21)00031-4en
dc.identifier.issn1474-4422
dc.identifier.otherPURE: 273717117
dc.identifier.otherPURE UUID: e557a76c-2bb6-4f5c-ab88-7cf7a3c32d47
dc.identifier.otherPubMed: 33773637
dc.identifier.otherORCID: /0000-0002-9502-9310/work/92020322
dc.identifier.otherScopus: 85103972083
dc.identifier.urihttps://hdl.handle.net/10023/23681
dc.descriptionFunding: This work, including collection and genotyping of the UK Young Lacunar Stroke DNA Study 2 (DNA Lacunar 2), was supported by a British Heart Foundation Programme Grant (RG/16/4/32218).en
dc.description.abstractBackground: 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.
dc.format.extent11
dc.language.isoeng
dc.relation.ispartofLancet Neurologyen
dc.rightsCopyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.en
dc.subjectQH426 Geneticsen
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.subjectDASen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.subject.lccQH426en
dc.subject.lccRC0321en
dc.titleGenetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studiesen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.identifier.doihttps://doi.org/10.1016/S1474-4422(21)00031-4
dc.description.statusPeer revieweden


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