Evidence map›Paper›PMID 33773637›Full record

SynthesisThe Lancet. Neurology2021

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

Matthew Traylor, Elodie Persyn, Liisa Tomppo, Sofia Klasson, Vida Abedi, Mark K Bakker, Nuria Torres, Linxin Li, Steven Bell, Loes Rutten-Jacobs and 35 more

Open access · hybridAbstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in The Lancet. Neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
126citing papers in PubMed, 5 pooled it
26.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

126 citing papers in PubMed, 5 syntheses or guidelines pooled it, 201 citations in OpenAlex.

  1. Does illicit drug use increase stroke risk? A systematic review, meta-analyses, and Mendelian randomization analysis.International journal of stroke : official journal of the International Stroke Society · 2026
    Pooled it
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  6. Observational
  7. Article
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  9. Multi-Omics Genome-Wide to Explore the Formation and Development Targets for Intracranial Aneurysms.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026
    Article
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  11. Review
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  13. Unravelling the genetic architecture of cerebral small vessel disease in the context of stroke.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026
    Review
  14. Article
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66 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

45 authors at 20 institutions in 10 countries.

Matthew TraylorClinical 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.
Elodie PersynDepartment of Medical and Molecular Genetics, King's College London, London, UK.
Liisa TomppoDepartment of Neurology, Helsinki University Hospital, Helsinki, Finland.
Sofia KlassonDepartment of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Vida AbediDepartment of Molecular and Functional Genomics, Weis Center for Research, Geisinger Health System, Danville, PA, USA.
Mark K BakkerDepartment of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
Nuria TorresStroke Pharmacogenomics and Genetics, Sant Pau Institute of Research, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
Linxin LiCentre for the Prevention of Stroke and Dementia, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.
Steven BellClinical Neurosciences, University of Cambridge, Cambridge, UK.
Loes Rutten-JacobsProduct Development Personalized Health Care, F Hoffmann-La Roche, Basel, Switzerland.
Daniel J TozerClinical Neurosciences, University of Cambridge, Cambridge, UK.
Christoph J GriessenauerNeuroscience Institute, Geisinger Health System, Danville, PA, USA; Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria.
Yanfei ZhangGenomic Medicine Institute, Geisinger Health System, Danville, PA, USA.
Annie PedersenDepartment of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Pankaj SharmaInstitute of Cardiovascular Research, Royal Holloway University of London, London, UK.
Jordi Jimenez-CondeNeurovascular Research Group, Department of Neurology of Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mediques), Universitat Autonoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
Tatjana RundekEvelyn F McKnight Brain Institute, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
Raji P GrewalNeuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, South Orange, NJ, USA.
Arne LindgrenDepartment of Neurology, Skane University Hospital, Lund, Sweden; Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
James F MeschiaDepartment of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Veikko SalomaaDepartment of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland.
Aki HavulinnaDepartment of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM HiLIFE), Helsinki, Finland.
Christina KourkoulisCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA; Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Katherine CrawfordCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Sandro MariniCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Braxton D MitchellDivision of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
Steven J KittnerDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
Jonathan RosandCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Martin DichgansInstitute for Stroke and Dementia Research (ISD), LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Christina JernDepartment of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Daniel StrbianDepartment of Neurology, Helsinki University Hospital, Helsinki, Finland; Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
Israel Fernandez-CadenasStroke Pharmacogenomics and Genetics, Sant Pau Institute of Research, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
Ramin ZandNeuroscience Institute, Geisinger Health System, Danville, PA, USA.
Ynte RuigrokDepartment of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
Natalia RostJ Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, USA.
Robin LemmensExperimental Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
Peter M RothwellCentre for the Prevention of Stroke and Dementia, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.
Christopher D AndersonCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Joanna WardlawCentre for Clinical Brain Sciences, UK Dementia Research Institute and Row Fogo Centre for Research into the Ageing Brain, University of Edinburgh, Edinburgh, UK.
Cathryn M LewisDepartment of Medical and Molecular Genetics, King's College London, London, UK; Social, Genetic, and Developmental Psychiatry Centre, King's College London, London, UK.
Hugh S MarkusClinical Neurosciences, University of Cambridge, Cambridge, UK. Electronic address: hsm32@medschl.cam.ac.uk.
Helsinki 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
Massachusetts General Hospital · USGeisinger Health System · USUniversity of Cambridge · GBUniversity of Gothenburg · SEHelsinki University Hospital · FIHospital de Sant Pau · ESKing's College London · GBUniversity Medical Center Utrecht · NLUniversity of Maryland, Baltimore · USUniversity of Oxford · GBBroad Institute · USFinnish Institute for Health and Welfare · FIHospital del Mar Research Institute · ESInstitute for Molecular Medicine Finland · FIMayo Clinic in Florida · USMunich Cluster for Systems Neurology · DEParacelsus Medical University · ATQueen Mary University of London · GBRoche (Switzerland) · CHRoyal Holloway University of London · GB

Funding

Research BaseP30DK072488 · NIDDK · UNIVERSITY OF MARYLAND BALTIMORE · PI MITCHELL, BRAXTON D, TAYLOR, SIMEON I. · 2005 to 2019
$17.3M
The NINDS International Stroke Genetics Consortium StudyU01NS069208 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI KITTNER, STEVEN J · 2010 to 2013
$9.4M
Sequencing Annotation and Functional Analysis in Risk of Intracerebral HemorrhageR01NS103924 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI ANDERSON, CHRISTOPHER DAVID · 2018 to 2022
$3.4M
Genetics of ischemic stroke in the SiGN ConsortiumR01NS100178 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI KITTNER, STEVEN J, MITCHELL, BRAXTON D · 2017 to 2021
$3.0M
Genetics of Early-Onset Ischemic Stroke ConsortiumR01NS105150 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI KITTNER, STEVEN J, MITCHELL, BRAXTON D · 2018 to 2022
$3.0M
CNV And Stroke (CaNVAS)R01NS114045 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI COLE, JOHN W. · 2020 to 2024
$2.6M
Genetic Analyses of Lipids in Cerebral Hemorrhage and Small Vessel DiseaseK23NS086873 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI ANDERSON, CHRISTOPHER DAVID · 2014 to 2018
$951k
BLRD VA I01 BX004672British Heart Foundation RG/16/4/32218Department of HealthMedical Research Council MR/J006971/1NIDDK NIH HHS P30 DK072488NINDS NIH HHS K23 NS086873NINDS NIH HHS R01 NS100178NINDS NIH HHS R01 NS103924NINDS NIH HHS R01 NS105150NINDS NIH HHS R01 NS114045NINDS NIH HHS U01 NS069208Wellcome TrustWellcome Trust 085475/B/08/ZWellcome Trust 085475/Z/08/ZWellcome Trust WT072952Wellcome Trust WT084724MAWellcome Trust WT088134/Z/09/A
6 · The paper itself

Abstract

backgroundThe 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.

methodsWe 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.

findingsOur 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.

interpretationLacunar 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.

fundingBritish Heart Foundation.

Indexed as

Genome-Wide Association StudyAustraliaEuropeGenetic Predisposition to DiseaseHumansMagnetic Resonance ImagingStroke, LacunarUnited States

Identifiers

PMID33773637
PMCPMC8062914
OpenAlexW3136867187

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.