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dc.contributor.authorTraylor, Matthew
dc.contributor.authorTozer, Daniel J
dc.contributor.authorCroall, Iain D
dc.contributor.authorLisiecka-Ford, Danuta M
dc.contributor.authorOlorunda, Abiodun Olubunmi
dc.contributor.authorBoncoraglio, Giorgio
dc.contributor.authorDichgans, Martin
dc.contributor.authorLemmens, Robin
dc.contributor.authorRosand, Jonathan
dc.contributor.authorRost, Natalia S
dc.contributor.authorRothwell, Peter M
dc.contributor.authorSudlow, Cathie LM
dc.contributor.authorThijs, Vincent
dc.contributor.authorRutten-Jacobs, Loes
dc.contributor.authorMarkus, Hugh S
dc.contributor.authorInternational Stroke Genetics Consortium
dc.date.accessioned2019-01-16T00:30:57Z
dc.date.available2019-01-16T00:30:57Z
dc.date.issued2019-02-19
dc.identifier.issn0028-3878
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/288032
dc.description.abstractOBJECTIVE: To identify novel genetic associations with white matter hyperintensities (WMH). METHODS: We performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels. RESULTS: We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013]; p = 1.6 × 10-8), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10-9). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03-1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00-1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; β [SE] = 0.106 [0.016]; p = 1.2 × 10-11 and rs7596872; β [SE] = 0.143 [0.021]; p = 3.4 × 10-12). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability. CONCLUSIONS: Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.
dc.description.sponsorshipThis work was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). Hugh Markus is supported by a National Institute for Health Research (NIHR) Senior Investigator award, and his work is supported by the Cambridge Universities NIHR Comprehensive Biomedical Research Centre. Loes Rutten-Jacobs was supported by a British Heart Foundation Immediate Research Fellowship (FS/15/61/31626). Natalia S. Rost is in part supported by NIH/NINDS R01NS086905 and R01NS082285. The MGH WMH study was supported by the National Institutes of Health (K23NS064052 - N.R.), American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (0775010N), and Deane Institute for Integrative Study of Atrial Fibrillation and Stroke. Robin Lemmens is a senior clinical investigator of FWO Flanders.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherOvid Technologies (Wolters Kluwer Health)
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectInternational Stroke Genetics Consortium
dc.subjectHumans
dc.subjectBrain Ischemia
dc.subjectPolymorphism, Single Nucleotide
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectStroke
dc.subjectGenome-Wide Association Study
dc.subjectCerebral Small Vessel Diseases
dc.subjectStroke, Lacunar
dc.subjectRho Guanine Nucleotide Exchange Factors
dc.subjectWhite Matter
dc.titleGenetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226).
dc.typeArticle
prism.endingPagee757
prism.issueIdentifier8
prism.publicationDate2019
prism.publicationNameNeurology
prism.startingPagee749
prism.volume92
dc.identifier.doi10.17863/CAM.35351
dcterms.dateAccepted2018-10-15
rioxxterms.versionofrecord10.1212/WNL.0000000000006952
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-02
dc.contributor.orcidThijs, Vincent [0000-0002-6614-8417]
dc.contributor.orcidRutten-Jacobs, Loes [0000-0003-3223-885X]
dc.identifier.eissn1526-632X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idBritish Heart Foundation (RG/16/4/32218)
pubs.funder-project-idStroke Association (PPA 2015/02)
pubs.funder-project-idBritish Heart Foundation (FS/15/61/31626)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Societal Challenges (667375)
cam.issuedOnline2019-01-18
cam.orpheus.successThu Jan 30 10:53:08 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International