Stroke Genetics Research Articles

Chapter 19 - Genetics in aphasia recovery

Considerable research efforts have been exerted toward understanding the mechanisms underlying recovery in aphasia. However, predictive models of spontaneous and treatment-induced recovery remain imprecise. Some of the hitherto unexplained variability in recovery may be accounted for with genetic data. A few studies have examined the effects of the BDNF val66met polymorphism on aphasia recovery, yielding mixed results. Advances in the study of stroke genetics and genetics of stroke recovery, including identification of several susceptibility genes through candidate-gene or genome-wide association studies, may have implications for the recovery of language function. The current chapter discusses both the direct and indirect evidence for a genetic basis of aphasia recovery, the implications of recent findings within the field, and potential future directions to advance understanding of the genetics-recovery associations.

Ischemic Stroke Genetics: What Is New and How to Apply It in Clinical Practice?

The etiology of ischemic stroke is multifactorial. Although receiving less emphasis, genetic causes make a significant contribution to ischemic stroke genesis, especially in early-onset stroke. Several stroke classification systems based on genetic information corresponding to various stroke phenotypes were proposed. Twin and family history studies, as well as candidate gene approach, are common methods to discover genetic causes of stroke, however, both have their own limitations. Genome-wide association studies and next generation sequencing are more efficient, promising and increasingly used for daily diagnostics. Some monogenic disorders, despite covering only about 7% of stroke etiology, may cause well-known clinical manifestations that include stroke. Polygenic disorders are more frequent, causing about 38% of all ischemic strokes, and their identification is a rapidly developing field of modern stroke genetics. Current advances in human genetics provide opportunity for personalized prevention of stroke and novel treatment possibilities. Genetic risk scores (GRS) and extended polygenic risk scores (PRS) estimate cumulative contribution of known genetic factors to a specific outcome of stroke. Combining those scores with clinical information and risk factor profiles might result in better primary stroke prevention. Some authors encourage the use of stroke gene panels for stroke risk evaluation and further stroke research. Moreover, new biomarkers for stroke genetic causes and novel targets for gene therapy are on the horizon. In this article, we summarize the latest evidence and perspectives of ischemic stroke genetics that could be of interest to the practitioner and useful for day-to-day clinical work.

Genetic and Genomic Epidemiology of Stroke in People of African Ancestry.

Stroke is one of the leading causes of disability and death worldwide and places a significant burden on healthcare systems. There are significant racial/ethnic differences in the incidence, subtype, and prognosis of stroke, between people of European and African ancestry, of which only about 50% can be explained by traditional stroke risk facts. However, only a small number of genetic studies include individuals of African descent, leaving many gaps in our understanding of stroke genetics among this population. This review article highlights the need for and significance of including African-ancestry individuals in stroke genetic studies and points to the efforts that have been made towards this direction. Additionally, we discuss the caveats, opportunities, and next steps in African stroke genetics—a field still in its infancy but with great potential for expanding our understanding of stroke biology and for developing new therapeutic strategies.

Abstract 9924: Polygenic Risk Score for PR Interval is Associated with Increased Risk of Ischemic Stroke

Atrial cardiomyopathy (AC) is an emerging risk factor for ischemic stroke (IS). We used polygenic risk scores (PRS) to study the association of the PR interval (PRI)-- an ECG marker for AC-- with IS and IS subtypes. We studied PRI, rather than other AC traits, because a validated multi-ethnic PRI-PRS exists. Methods: We calculated PRI-PRS for patients in the NINDS Stroke Genetics Network (SiGN) database, which contains well-characterized stroke patients and in which we have found an association of a PRS for atrial fibrillation with IS subtypes. We derived PRS for 10 GWAS thresholds after a clumping procedure to eliminate SNPs in linkage disequilibrium. SNPs were weighted by their beta coefficients from the GWAS summary statistics to generate PRS. We normalized by the number of SNPs included. We used logistic regression to compare PRI-PRS in stroke cases (n=13930) and non-stroke controls (n=49473). We controlled for sex and the first 10 principal components of genetic ancestry. We stratified by genetic ancestry and genotype platforms. Logistic regression analyses for each stratum were meta-analyzed using an inverse-variance weighting-based method, assuming fixed effects. Results and Conclusions: In the overall meta-analysis, PRI-PRS was weakly associated with increased risk of IS (p<0.02, only for one GWAS threshold). PRI-PRS was associated with increased risk of IS due to small artery occlusion (SAO) (p=0.032 and 0.033, using GWAS of PRI p-value thresholds 0.05 and 0.005 respectively), but not with other IS subtypes. The SAO association may reflect the association of PRI and hypertension, a risk factor for SAO. In a secondary analysis of European strata, we observed a robust association (p<0.02 across all GWAS thresholds) of the PRI-PRS with all IS in GEOS, which consists of younger onset strokes (age of stroke onset < 50 years). PRI-PRS was also associated in GEOS (p<0.01 across all GWAS thresholds) with the subtype of strokes of undetermined origin, which includes embolic strokes of unknown source (ESUS). PRI-PRS was also associated with large artery strokes at some GWAS thresholds in GEOS. Our results suggest that genetic risk for prolonged PRI is associated with SAO and may have more robust associations with other stroke subtypes in some populations.

Abstract 11229: Clinical and Genetic Atrial Fibrillation Risk and Discrimination of Cardioembolic from Non-Cardioembolic Stroke

Introduction: Prior studies demonstrate correlation between atrial fibrillation (AF) polygenic risk score (PRS) and ischemic stroke, especially cardioembolic (CE) stroke, suggesting shared genetic components. In this study, we hypothesized that an AF PRS can discriminate CE from non-CE strokes. Methods: We evaluated AF and stroke risk in 26,145 individuals of European descent from the NINDS Stroke Genetics Network (SiGN) with study-adjudicated TOAST subtypes. AF genetic risk was estimated using two newly derived PRS (LDpred-funct and sBayesR) and two previously validated PRS (pruning and thresholding and LDpred). A clinical risk score (CRS) was derived within separate individuals in UK Biobank utilizing components of the Cohorts for Aging and Genomic Research in Epidemiology (CHARGE-AF) model available in SiGN. We regressed each AF PRS on AF status and separately CE stroke in logistic regression models adjusted for CRS, imputation group, and the first 10 principal components. We calculated discrimination of AF and CE stroke, and compared across models using 2000-iteration bootstrapping and pairwise Z-testing. We also assessed category-free reclassification of CE stroke risk with the addition of PRS to a) CRS, and b) a modified CHA 2 DS 2 -VASc score including all available score components. Results: Each AF PRS was significantly associated with AF and CE stroke after adjustment for the CRS. Addition of any AF PRS significantly improved model discrimination as compared to the CRS alone, and LDpred discriminated both AF and CE better than other PRSs ( Figure ; P <0.005). Adding LDpred PRS to CRS resulted in appropriate reclassification of CE stroke risk compared to the CRS or the modified CHA 2 DS 2 -VASc score alone ( Figure ). Conclusions: Addition of AF polygenic risk to clinical risk factors improves discrimination of CE from non-CE strokes, as well as reclassification of stroke subtype. AF polygenic risk may be a useful biomarker for identifying AF-related strokes.

Genetically determined risk of mood swings and cardiometabolic diseases: mendelian randomization study

Abstract Background Mood swings is believed to associated with increased risk of Cardiometabolic Diseases (CMD). However, the roles of mood swings on CMD are controversial because of the bias of reverse causation and/or confounding in epidemiological studies. Hence, we use a two-sample MR approach to identify the causal association between genetically determined mood swings and CMD. Methods We obtained 33 independent single-nucleotide polymorphisms (SNPs) with genome-wide significant (P<5×10–8) associated with mood swings as instrumental variable in UK Biobank. Summary data of outcomes were extracted from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics consortium, the Diabetes Genetics Replication and Meta-analysis consortium, the CKDGen consortium, and the International Stroke Genetics Consortium. Results The genetic instrument of 33 SNPs explained 4.8% of the variance in mood swings. Genetically determined mood swings was associated with an increased risk of coronary artery disease (CAD) (odds ratio 3.12, 95% confidence interval 1.92 to 5.08; P=4.32×10–6). However, mood swings had no effect on the other cardiometabolic outcomes. The above estimates were consistent across all three MR methods without significant heterogeneity. Also, there was no evidence of directional pleiotropy for each outcome except for large artery stroke. Conclusions Using MR approaches that are able draw causal inference, our results suggest that interventions aimed at improving mood swings in the population would lead to a reduction risk of CAD, which highlights the importance of mood management in high-risk CAD population. Funding Acknowledgement Type of funding sources: None.

Stroke in Africa: profile, progress, prospects and priorities.

Stroke is a leading cause of disability, dementia and death worldwide. Approximately 70% of deaths from stroke and 87% of stroke-related disability occur in low-income and middle-income countries. At the turn of the century, the most common diseases in Africa were communicable diseases, whereas non-communicable diseases, including stroke, were considered rare, particularly in sub-Saharan Africa. However, evidence indicates that, today, Africa could have up to 2–3-fold greater rates of stroke incidence and higher stroke prevalence than western Europe and the USA. In Africa, data published within the past decade show that stroke has an annual incidence rate of up to 316 per 100,000, a prevalence of up to 1,460 per 100,000 and a 3-year fatality rate greater than 80%. Moreover, many Africans have a stroke within the fourth to sixth decades of life, with serious implications for the individual, their family and society. This age profile is particularly important as strokes in younger people tend to result in a greater loss of self-worth and socioeconomic productivity than in older individuals. Emerging insights from research into stroke epidemiology, genetics, prevention, care and outcomes offer great prospects for tackling the growing burden of stroke on the continent. In this article, we review the unique profile of stroke in Africa and summarize current knowledge on stroke epidemiology, genetics, prevention, acute care, rehabilitation, outcomes, cost of care and awareness. We also discuss knowledge gaps, emerging priorities and future directions of stroke medicine for the more than 1 billion people who live in Africa.

Stroke Genetics: Turning Discoveries into Clinical Applications.

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.

Identifying novel genetic risk loci for lacunar stroke

In The Lancet Neurology, Matthew Traylor and colleagues 1 Traylor M Persyn E Tomppo L et al. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. Lancet Neurol. 2021; (published online March 25.)https://doi.org/10.1016/S1474-4422(21)00031-4 Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar report the results of the largest pooled analysis of risk genes for lacunar stroke published to date. The authors included more than 7000 patients with lacunar stroke and 250 000 controls. In almost 3000 cases, MRI confirmed the presence of lacunar stroke. Patients were recruited from the UK DNA Lacunar Stroke studies 1 and 2 and by the collaborators of the International Stroke Genetics Consortium. The authors did a genome-wide association study (GWAS) for lacunar stroke alone, as well as a multi-trait approach with a phenotype including both lacunar strokes and white matter hyperintensities. They also did a transcriptome-wide association study, which identified transcribed genes related to lacunar stroke. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studiesLacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. Full-Text PDF Open Access

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

SummaryBackgroundThe genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease.MethodsWe did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.FindingsOur meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke.InterpretationLacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk.FundingBritish Heart Foundation.

Abstract P663: Polygenic Risk Scores for Plasma Levels of Fibrin D-Dimer and Tissue Plasminogen Activator Are Associated With Non-Lacunar Stroke

Introduction: Plasma concentrations of prothrombotic factors such as fibrinogen have previously been associated with ischemic stroke risk. To extend this observation, we examined the association of polygenic risk scores (PRS) for increased plasma levels of thrombosis-related factors with ischemic stroke. Our hypotheses were that these PRS would be more associated with early than late onset stroke and with non-lacunar than lacunar stroke. Methods: We identified 9053 late onset (≥ 60 years) stroke cases from the NINDS International Stroke Genetics Consortium (SiGN) with 24804 controls and 6594 early onset (&lt; 60 years) stroke cases from the Genetics of Early Onset Ischemic Stroke Consortium with 30561 controls. We identified previously known loci associated with plasma levels of four thrombosis-related factors: fibrinogen, fibrin D-dimer, tPA and PAI-1 from prior GWAS studies and developed genome-wide PRS for plasma concentrations of these factors. We then used logistic regression to test the association of these scores with risk of stroke and stroke subtype. Results: PRS for fibrin D dimer levels were associated with increased risk for all stroke and specifically for older (p = 0.019), but not younger (p = 0.22) onset stroke. PRS for tPA levels were also marginally associated with older (p = 0.06), but not younger (p = 0.24) onset stroke. Genetic risk scores for both D dimer and tPA were associated with non-lacunar stroke (Table 1). Further analyses stratified by age revealed PRS for D dimer to be significantly associated with non-lacunar stroke (but not lacunar stroke) in both late and early onset cohorts. PRS for fibrinogen and PAI-1 were not associated with stroke. Conclusion: Genomic risk scores for thrombosis-related factors including D dimer and tPA levels were associated with risk for ischemic stroke, and specifically, non-lacunar stroke.

The Role of C-Reactive Protein and Fibrinogen in the Development of Intracerebral Hemorrhage: A Mendelian Randomization Study in European Population.

Background: The causal association of C-reactive protein (CRP) and fibrinogen on intracerebral hemorrhage (ICH) remains uncertain. We investigated the causal associations of CRP and fibrinogen with ICH using two-sample Mendelian randomization.Method: We used single-nucleotide polymorphisms associated with CRP and fibrinogen as instrumental variables. The summary data on ICH were obtained from the International Stroke Genetics Consortium (1,545 cases and 1,481 controls). Two-sample Mendelian randomization estimates were performed to assess with inverse-variance weighted and sensitive analyses methods including the weighted median, the penalized weighted median, pleiotropy residual sum and outlier (MR-PRESSO) approaches. MR-Egger regression was used to explore the pleiotropy.Results: The MR analyses indicated that genetically predicted CRP concentration was not associated with ICH, with an odds ratio (OR) of 1.263 (95% CI = 0.935–1.704, p = 0.127). Besides, genetically predicted fibrinogen concentration was not associated with an increased risk of ICH, with an OR of 0.879 (95% CI = 0.060–18.281; p = 0.933). No evidence of pleiotropic bias was detected by MR-Egger. The findings were overall robust in sensitivity analyses.Conclusions: Our findings did not support that CRP and fibrinogen are causally associated with the risk of ICH.

Exome Array Analysis of Early-Onset Ischemic Stroke.

The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease. Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases. Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10-6). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10-7), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10-7) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10-6). Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.

Sleep Duration and Stroke: Prospective Cohort Study and Mendelian Randomization Analysis.

Studies of sleep duration in relation to specific types of stroke are scarce. Moreover, the results are inconclusive and causality remains unclear. Our objective was to investigate whether sleep duration is associated with risk of stroke and its types using observational and Mendelian randomization designs. The prospective study included 79 881 women and men (45-79 years of age) who were followed up for incident stroke or death over a mean follow-up of 14.6 years (1 164 646 person-years) through linkage to Swedish Registers. For the Mendelian randomization study, single-nucleotide polymorphisms associated with sleep duration were identified from a genome-wide association study. Summarized data for genetic associations with stroke were obtained from publicly available data of the MEGASTROKE and the International Stroke Genetics Consortia. Compared with normal sleep duration, long sleep (≥9 hours per day) was associated with increased risk of total and ischemic stroke (hazard ratios [95% CI], 1.12 [1.03-1.22] and 1.14 [1.03-1.24], respectively), whereas short sleep (<7 h/d) was linked to higher risk of intracerebral hemorrhage (hazard ratio [95% CI], 1.21 [1.03-1.41]). The 2-sample Mendelian randomization analysis supported no causal association of short or long sleep duration with ischemic stroke as a whole. In a prospective study, long sleep duration was associated with increased risk of total and ischemic stroke, whereas short sleep was linked to increased risk of intracerebral hemorrhage. However, the Mendelian randomization analysis did not show a significant detrimental effect of short or long sleep duration on the risk of total stroke or stroke types.

Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke.

Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

Diffusion-Weighted Imaging, MR Angiography, and Baseline Data in a Systematic Multicenter Analysis of 3,301 MRI Scans of Ischemic Stroke Patients-Neuroradiological Review Within the MRI-GENIE Study.

Background: Magnetic resonance imaging (MRI) serves as a cornerstone in defining stroke phenotype and etiological subtype through examination of ischemic stroke lesion appearance and is therefore an essential tool in linking genetic traits and stroke. Building on baseline MRI examinations from the centralized and structured radiological assessments of ischemic stroke patients in the Stroke Genetics Network, the results of the MRI-Genetics Interface Exploration (MRI-GENIE) study are described in this work.Methods: The MRI-GENIE study included patients with symptoms caused by ischemic stroke (N = 3,301) from 12 international centers. We established and used a structured reporting protocol for all assessments. Two neuroradiologists, using a blinded evaluation protocol, independently reviewed the baseline diffusion-weighted images (DWIs) and magnetic resonance angiography images to determine acute lesion and vascular occlusion characteristics.Results: In this systematic multicenter radiological analysis of clinical MRI from 3,301 acute ischemic stroke patients according to a structured prespecified protocol, we identified that anterior circulation infarcts were most prevalent (67.4%), that infarcts in the middle cerebral artery (MCA) territory were the most common, and that the majority of large artery occlusions 0 to 48 h from ictus were in the MCA territory. Multiple acute lesions in one or several vascular territories were common (11%). Of 2,238 patients with unilateral DWI lesions, 52.6% had left-sided infarct lateralization (P = 0.013 for χ2 test).Conclusions: This large-scale analysis of a multicenter MRI-based cohort of AIS patients presents a unique imaging framework facilitating the relationship between imaging and genetics for advancing the knowledge of genetic traits linked to ischemic stroke.

Proceedings of the 26th International Stroke Genetics Consortium Workshop: St. Louis, MO

The 26th workshop of the International Stroke Genetics Consortium (ISGC) was held at the Four Seasons Hotel on November 2–4, 2019 in St. Louis, MO, and was hosted by Jin-Moo Lee, MD, PhD and Carlos Cruchaga, PhD, and co-hosted by Stephanie Debette, MD, PhD. The ISGC is an international collaboration of physicians and scientists who have agreed to pool resources and expertise in an effort to unravel the genetic basis of stroke and its comorbidities. Founded in 2007 by a small group of stroke genetics investigators, the ISGC has grown to over 200 members representing over 50 countries in North and South America, Europe, Australia, Africa, and Asia. ISGC workshops are held semi-annually and provide a forum for ISGC investigators to report on progress of ongoing scientific projects and discuss new ideas that help advance the ISGC's research mission. The ISGC nurtures junior investigators by offering several travel awards to young investigators interested in stroke genetics. Many abstracts in these Proceedings reflect the contributions of active junior investigators. Herein, we present the Proceedings and official published abstracts of the 26th ISGC Workshop.

Proceedings of the 25th International Stroke Genetics Consortium Workshop: Cambridge, UK

The 25th workshop of the International Stroke Genetics Consortium (ISGC) was held at the beautiful and historic Queens' College, University of Cambridge, UK on April 10–12, 2019, and was hosted by Associate Professor Jemma C Hopewell, Dr Matthew Traylor, and Professor Hugh Markus, and co-hosted by Professor Jin-Moo Lee and Associate Professor Carlos Cruchaga. Herein, we present the Proceedings and official published abstracts of the 25th ISGC Workshop.

Effects of Genetic Variants on Stroke Risk.

Effects of Genetic Variants on Stroke Risk.