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

During 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 also 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 early 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 that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe

Early neurological change after ischemic stroke is associated with 90-day outcome

BACKGROUND AND PURPOSE: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in NIH stroke scale score (NIHSS) from baseline to 24 hours (baseline – 24h = ΔNIHSS(6–24h)), to examine its relevance to AIS mechanisms and long-term outcomes. METHODS: Patients with NIHSS prospectively recorded within 6h after onset and then 24h later were enrolled in the GENISIS (Genetics of Early Neurological InStability after Ischemic Stroke) study. Stepwise linear regression determined variables that independently influenced ΔNIHSS(6–24h). In a subcohort of tPA-treated patients with large vessel occlusion (LVO), the influence of early sustained recanalization and hemorrhagic transformation (HT) on ΔNIHSS(6–24h) was examined. Finally, the association of ΔNIHSS(6–24h) with 90-day favorable outcomes (modified Rankin scale score 0–2) was assessed. Independent analysis was performed using data from the two NINDS tPA stroke trials. RESULTS: For 2555 AIS patients, median baseline NIHSS was 9 (IQR 4–16) and median ΔNIHSS(6–24h) was 2 (IQR 0–5). In a multivariable model, baseline NIHSS, tPA treatment, age, glucose, site and systolic blood pressure independently predicted ΔNIHSS(6–24h) (R(2)=0.15). In the LVO subcohort, early sustained recanalization and HT increased the explained variance (R(2)=0.27), but much of the variance remained unexplained. ΔNIHSS(6–24h) had significant and independent association with 90-day favorable outcome. For the subjects in the two NINDS tPA trials, ΔNIHSS(3–24h) was similarly associated with 90-day outcomes. CONCLUSIONS: The dynamic phenotype, ΔNIHSS(6–24h), captures both explained and unexplained mechanisms involved in AIS, and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS(6–24h) promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS

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

Funding: This work was supported by grants from the Emergency Medicine Foundation Career Development Grant; AHA Mentored Clinical & Population Research Award (14CRP18860027); NIH/NINDS-R01-NS085419 (C.C., J.M.L.); NIH/NINDS-R37-NS107230, NIH/NINDS U24-NS107230 (J.M.L.); NIH/NINDS-K23-NS099487 (L.H.); NIH/NIA-K99-AG062723 (L.I.); Barnes-Jewish Hospital Foundation (J.M.L.); Biogen (C.C., J.M.L.); Bright Focus Foundation, US Department of Defense, Helsinki University Central Hospital; Finnish Medical Foundation; Finland government subsidiary funds; Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (grants ‘Registro BASICMAR’ Funding for Research in Health (PI051737), ‘GWALA project’ from Fondos de Investigación Sanitaria ISC III (PI10/02064, PI12/01238 and PI15/00451), JR18/00004); Fondos FEDER/EDRF Red de Investigación Cardiovascular (RD12/0042/0020); Fundació la Marató TV3; Genestroke Consortium (76/C/2011); Recercaixa’13 (JJ086116). Tomás Sobrino (CPII17/00027), Francisco Campos (CPII19/00020) and Israel Fernandez are supported by Miguel Servet II Program from Instituto de Salud Carlos III and Fondos FEDER. I.F. is also supported by Maestro project (PI18/01338) and Pre-test project (PMP15/00022) from Instituto de Salud Carlos III and Fondos Feder, Agaur; and Epigenesis project from Marató TV3 Foundation. J.C., J.M., A.D., J.M.-F., J.A. and I.F. are supported by Invictus plus Network (RD16/0019) from Instituto de Salud Carlos III and Fondos Feder. Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-2013/07559-3) (I.L.-C.), Sigrid Juselius Foundation. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. B.S., B.A. and F.S. are supported by NIH awards NS097000, NS101718, NS075035, NS079153 and NS106950.During 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 6h of stroke onset and NIHSS at 24h.  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 24h of variance was explained by common genetic variations, and also 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 early 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 that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability.  These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke.PostprintPeer reviewe

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

During 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 also 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 early 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 that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe

Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke

During 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 NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each loci. eQTL mapping and SMR indicate that ADAM23 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1 (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated PARK2 (LBF=5.30) and ABCB5 (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23 , a pre-synaptic protein, and GRIA1 , a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke.RESEARCH INTO CONTEXT: Evidence before this study: No previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke.Added Value of this study: This is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry.Implications of all available evidence: The findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.</p