Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226)
| Autor: | Traylor, M, Tozer, D, Croall, I, Lisiecka-Ford, D, Olorunda, A, Boncoraglio, G, Dichgans, M, Lemmens, R, Rosand, J, Rost, N, Rothwell, P, Sudlow, C, Thijs, V, Rutten-Jacobs, L, Markus, H, Consortium, International Stroke Genetics |
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| Přispěvatelé: | Thijs, Vincent [0000-0002-6614-8417], Rutten-Jacobs, Loes [0000-0003-3223-885X], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male genetics [Stroke Lacunar] genetics [Rho Guanine Nucleotide Exchange Factors] genetics [Brain Ischemia] Polymorphism Single Nucleotide PLEKHG1 protein human diagnostic imaging [White Matter] Brain Ischemia diagnostic imaging [Stroke] Humans ddc:610 diagnostic imaging [Stroke Lacunar] Aged Middle Aged White Matter Stroke diagnostic imaging [Brain Ischemia] Cerebral Small Vessel Diseases Stroke Lacunar genetics [Stroke] genetics [Cerebral Small Vessel Diseases] Female diagnostic imaging [Cerebral Small Vessel Diseases] Rho Guanine Nucleotide Exchange Factors Genome-Wide Association Study |
| Zdroj: | Neurology 92(8), e749-e757 (2019). doi:10.1212/WNL.0000000000006952 |
| DOI: | 10.1212/WNL.0000000000006952 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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