Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.
OBJECTIVE: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. METHODS: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. RESULTS: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)). CONCLUSIONS: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.
Traylor, M; Zhang, CR; Adib-Samii, P; Devan, WJ; Parsons, OE; Lanfranconi, S; Gregory, S; Cloonan, L; Falcone, GJ; Radmanesh, F; Fitzpatrick, K; Kanakis, A; Barrick, TR; Moynihan, B; Lewis, CM; Boncoraglio, GB; Lemmens, R; Thijs, V; Sudlow, C; Wardlaw, J; Rothwell, PM; Meschia, JF; Worrall, BB; Levi, C; Bevan, S; Furie, KL; Dichgans, M; Rosand, J; Markus, HS; Rost, N; International Stroke Genetics Consortium,
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