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Neurology. 2019 Feb 19;92(8):e749-e757. doi: 10.1212/WNL.0000000000006952. Epub 2019 Jan 18.

Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226).

Author information

1
From the Department of Clinical Neurosciences, Stroke Research Group (M.T., D.J.T., I.D.C., D.M.L.F., A.O.O., L.R.-J., H.S.M.), University of Cambridge, UK; Department of Cerebrovascular Diseases (G.B.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Institute for Stroke and Dementia Research (M.D.), Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich; German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany; Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND) (R.L.), KU Leuven-University of Leuven; Department of Neurology (R.L.), University Hospitals Leuven; Laboratory of Neurobiology (R.L.), VIB Center for Brain and Disease Research, Leuven, Belgium; Center for Human Genetic Research (J.R.) and Division of Neurocritical Care and Emergency Neurology (J.R.) and J. Philip Kistler Stroke Research Center (J.R., N.S.R.), Department of Neurology, Massachusetts General Hospital, Boston; Nuffield Department of Clinical Neurosciences (Clinical Neurology), Stroke Prevention Research Unit (P.M.R.), University of Oxford; Centre for Clinical Brain Sciences and Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Stroke Division, Florey Institute of Neuroscience and Mental Health (V.T.), University of Melbourne; and Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia. MT628@medschl.cam.ac.uk.
2
From the Department of Clinical Neurosciences, Stroke Research Group (M.T., D.J.T., I.D.C., D.M.L.F., A.O.O., L.R.-J., H.S.M.), University of Cambridge, UK; Department of Cerebrovascular Diseases (G.B.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Institute for Stroke and Dementia Research (M.D.), Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich; German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany; Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND) (R.L.), KU Leuven-University of Leuven; Department of Neurology (R.L.), University Hospitals Leuven; Laboratory of Neurobiology (R.L.), VIB Center for Brain and Disease Research, Leuven, Belgium; Center for Human Genetic Research (J.R.) and Division of Neurocritical Care and Emergency Neurology (J.R.) and J. Philip Kistler Stroke Research Center (J.R., N.S.R.), Department of Neurology, Massachusetts General Hospital, Boston; Nuffield Department of Clinical Neurosciences (Clinical Neurology), Stroke Prevention Research Unit (P.M.R.), University of Oxford; Centre for Clinical Brain Sciences and Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Stroke Division, Florey Institute of Neuroscience and Mental Health (V.T.), University of Melbourne; and Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia.
#
Contributed equally

Abstract

OBJECTIVE:

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.

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