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Sökning: WFRF:(Mitchell Braxton D.) > (2020-2021) > Strbian Daniel > Genetic basis of la...

  • Traylor, MatthewQueen Mary University (författare)

Genetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studies

  • Artikel/kapitelEngelska2021

Förlag, utgivningsår, omfång ...

  • 2021
  • 11 s.

Nummerbeteckningar

  • LIBRIS-ID:oai:lup.lub.lu.se:b561ec4a-e357-477a-ac72-8e58e18e96f2
  • https://lup.lub.lu.se/record/b561ec4a-e357-477a-ac72-8e58e18e96f2URI
  • https://doi.org/10.1016/S1474-4422(21)00031-4DOI
  • https://gup.ub.gu.se/publication/308532URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:art swepub-publicationtype
  • Ämneskategori:ref swepub-contenttype

Anmärkningar

  • 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 och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Persyn, ElodieKing's College London (författare)
  • Tomppo, LiisaHelsinki University Central Hospital (författare)
  • Klasson, SofiaGothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine (författare)
  • Abedi, VidaSigfried and Janet Weis Center for Research (författare)
  • Bakker, Mark K.University Medical Center Utrecht (författare)
  • Torres, NuriaHospital de Sant Pau (författare)
  • Li, LinxinUniversity of Oxford (författare)
  • Bell, StevenUniversity of Cambridge (författare)
  • Rutten-Jacobs, LoesF. Hoffmann-La Roche AG (författare)
  • Tozer, Daniel J.University of Cambridge (författare)
  • Jern, Christina,1962Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine(Swepub:gu)xjerch (författare)
  • Zhang, YanfeiGeisinger Health System (författare)
  • Pedersen, Annie,1981Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine(Swepub:gu)xpeder (författare)
  • Sharma, PankajRoyal Holloway University of London (författare)
  • Jimenez-Conde, JordiAutonomous University of Barcelona,Pompeu Fabra University (författare)
  • Rundek, TatjanaUniversity of Miami (författare)
  • Grewal, Raji P.Seton Hall University (författare)
  • Lindgren, ArneLund University,Lunds universitet,Klinisk strokeforskning,Forskargrupper vid Lunds universitet,Clinical Stroke Research Group,Lund University Research Groups,Skåne University Hospital(Swepub:lu)neur-ali (författare)
  • Meschia, James F.Mayo Clinic Florida (författare)
  • Salomaa, VeikkoFinnish National Institute for Health and Welfare (författare)
  • Havulinna, AkiFinnish National Institute for Health and Welfare,Institute for Molecular Medicine Finland (FIMM) (författare)
  • Kourkoulis, ChristinaBroad Institute,Massachusetts General Hospital (författare)
  • Crawford, KatherineMassachusetts General Hospital,Broad Institute (författare)
  • Marini, SandroMassachusetts General Hospital,Broad Institute (författare)
  • Mitchell, Braxton D.Baltimore Veterans Administration Medical Center,University of Maryland School of Medicine (författare)
  • Kittner, Steven J.University of Maryland School of Medicine,Baltimore Veterans Administration Medical Center (författare)
  • Rosand, JonathanBroad Institute,Massachusetts General Hospital (författare)
  • Dichgans, MartinLudwig-Maximilian University of Munich,Munich Cluster for Systems Neurology (författare)
  • Jern, ChristinaUniversity of Gothenburg (författare)
  • Strbian, DanielHelsinki University Central Hospital,University of Helsinki (författare)
  • Fernandez-Cadenas, IsraelAutonomous University of Barcelona,Hospital de Sant Pau (författare)
  • Zand, RaminGeisinger Health System (författare)
  • Ruigrok, YnteUniversity Medical Center Utrecht (författare)
  • Rost, NataliaMassachusetts General Hospital (författare)
  • Lemmens, RobinUniversity Hospitals Leuven,Catholic University of Leuven (författare)
  • Rothwell, Peter M.University of Oxford (författare)
  • Anderson, Christopher D.Massachusetts General Hospital,Broad Institute (författare)
  • Wardlaw, JoannaUniversity of Edinburgh (författare)
  • Lewis, Cathryn M.King's College London (författare)
  • Markus, Hugh S.University of Cambridge (författare)
  • Queen Mary UniversityKing's College London (creator_code:org_t)
  • Helsinki Stroke
  • National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network
  • UK DNA Lacunar Stroke Study Investigators
  • International Stroke Genetics Consortium

Sammanhörande titlar

  • Ingår i:The Lancet Neurology20:5, s. 351-3611474-4422

Internetlänk

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