Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

AbstractDuring the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6  h of stroke onset and NIHSS at 24 h.A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and a lso that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence earl y change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate thatADAM23 (log Bayes factor  = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested thatGRIA1 (log Bayes factor  = 5.19), which is predominantly expressed in the brain, is the gene driving the as...
Source: Brain - Category: Neurology Source Type: research