Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke

Abstract

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.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

“…9 and 10). Prior studies have demonstrated that variants in this region are associated with white-matter hyperintensity (WMH) burden 17 , a brain magnetic resonance imaging marker of small-vessel disease (SVD).…”

Genetics of vascular dementia – review from the ICVD working group

“…Interestingly, genes at these loci are implicated in both AD and in (hemorrhagic) stroke [46]. Earlier findings have been replicated in independent population-based [47, 48] and clinical [49] samples. The CHARGE consortium also investigated whether genetic influences could be detected for the progression of white matter hyperintensities over time [50].…”

Genetic variation at 16q24.2 is associated with small vessel stroke

“…Jonathan Rosand, 5,6,7,48 Steven J. Kittner, 24 Braxton D. Mitchell, 61,62 Martin Dichgans, 2,63 Bradford B. Worrall, 64 and Hugh S. Markus 65 ; on behalf of the International Stroke Genetics Consortium Objective: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment.…”