Year: 2019
Type: article
Study design: Observational Study
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.
Source: Neurology
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,603
Funders: National Science Foundation, U.S. Department of Veterans Affairs, American Heart Association, Eli Lilly and Company, Västra Götalandsregionen, Universität Basel, Helsingin ja Uudenmaan Sairaanhoitopiiri, Suomen Lääketieteen Säätiö, Alfred Kordelinin Säätiö, Maud Kuistilan Muistosäätiö, Aarne Koskelon Säätiö, National Institute for Health and Care Research, British Heart Foundation, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Fonds Wetenschappelijk Onderzoek, Lunds Universitet, Biomedicum Helsinki-säätiö, Päivikki ja Sakari Sohlbergin Säätiö, Vetenskapsrådet, Schweizerische Herzstiftung, Fondation de France, Emil Aaltosen Säätiö, Orionin Tutkimussäätiö, Aarne ja Aili Turusen Säätiö, Schweizerische Akademie der Medizinischen Wissenschaften, STROKE-Riksförbundet, Skånes universitetssjukhus, Vlaamse regering, Centre hospitalier régional universitaire de Lille, National Institutes of Health, Medical Research Council, National Institute of Neurological Disorders and Stroke
Awards: NIHR Senior Investigator Award, NIHR Senior Investigator Award, Identification of novel pathophysiological mechanisms in cerebral small vessel disease: an epidemiologic and genetic approach, UK Biobank (core renewal), Using genetics to explore the pathophysiology of cerebral small vessel disease. 15
OpenAlex ID: W2910949799