Large Artery Stroke Research Articles

Migraine, Stroke, and Cervical Arterial Dissection: Shared Genetics for a Triad of Brain Disorders With Vascular Involvement.

Background and ObjectivesMigraine, stroke, and cervical artery dissection (CeAD) represent a triad of cerebrovascular disorders with pairwise comorbid relationships and vascular involvement. Larger samples and recent advances in methodology invite systematic exploration of their shared genetics.MethodsGenetic analyses leveraged summary statistics from genome-wide association studies of the largest available samples of each disorder, including subtypes of stroke (ischemic stroke, large artery stroke, small vessel stroke, and cardioembolic stroke) and migraine (with aura and without aura). For each pair of disorders, genetic correlation was assessed both on a genome-wide basis and within independent segments across the genome including known specific loci for each disorder. A cross-trait meta-analysis was used to identify novel candidate loci. Finally, potential causality of migraine susceptibility on stroke and CeAD was assessed by Mendelian randomization.ResultsAmong all pairs of disorders, genome-wide genetic correlation was observed only between CeAD and migraine, particularly MO. Local genetic correlations were more extensive between migraine and CeAD than those between migraine and stroke or CeAD and stroke and revealed evidence for novel CeAD associations at rs6693567 (ADAMTSL4/ECM1), rs11187838 (PLCE1), and rs7940646 (MRVI1) while strengthening prior subthreshold evidence at rs9486725 (FHL5) and rs650724 (LRP1). At known migraine loci, novel associations with stroke had concordant risk alleles for small vessel stroke at rs191602009 (CARF) and for cardioembolic stroke at rs55884259 (NKX2-5). Known migraine loci also revealed novel associations but with opposite risk alleles for all stroke, ischemic stroke, and small vessel stroke at rs55928386 (HTRA1), for large artery stroke at rs11172113 (LRP1), and for all stroke and ischemic stroke at rs1535791 and rs4942561 (both LRCH1), respectively. rs182923402 (near PTCH1) was a novel concordant locus for migraine and cardioembolic stroke. Mendelian randomization supported potential causal influences of migraine on CeAD (odds ratio [95% confidence interval] per doubling migraine prevalence = 1.69 [1.24–2.3], p = 0.0009) with concordant risk, but with opposite risk on large artery stroke (0.86 [0.76–0.96], p = 0.0067).DiscussionThe findings emphasize shared genetic risk between migraine and CeAD while identifying loci with likely vascular function in migraine and shared but opposite genetic risk between migraine and stroke subtypes, and a central role of LRP1 in all 3 cerebrovascular disorders.

Cardiac Troponin I and Risk of Stroke: A Mendelian Randomization Study.

PurposeCardiac troponin I (cTnI) is a well-established biomarker for stroke prediction, especially in patients with heart diseases. However, the causal effect of circulating cTnI on stroke remains unclear.MethodsWe employed Mendelian Randomization (MR) analysis to determine the associations between genetically predicted circulating cTnI levels and stroke and its subtypes. Summary-level data for exposure and outcomes were generated from different genome-wide association studies. Single-nucleotide polymorphisms (SNPs) associated with circulating cTnI at genome-wide significance level (P < 5 × 10−8) were employed as instrumental variables (IVs). We used fixed-effect inverse-variance weighted (IVW) as the main method for pooling MR estimates. Sensitivity analyses and multivariable MR analyses were carried out to assess the robustness of the results.ResultsUsing the fixed-effects IVW method, we found that genetically elevated plasma cTnI levels may have a causal effect on the risk of cardioembolic stroke (CES) (odds ratio (OR), 1.58; 95% confidence interval (CI), 1.17–2.13; P = 0.003). Additional analyses including multiplicative random-effects (mre) IVW, weighted median, MR-Egger and MR-PRESSO yielded similar results, but with broader CIs that span 1.0. The total effect of cTnI on CES was attenuated by adjusting for the effect of atrial fibrillation (OR,1.26; 95% CI, 0.76–2.11; P = 0.371) and smoking (OR,1.53; 95% CI, 0.87–2.66; P = 0.137). In addition, we found no causal effect of cTnI on the risk of any stroke and other stroke subtypes, including any ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, and intracerebral hemorrhage. These results were consistent across sensitivity analyses.ConclusionThis study provides little evidence that increased serum cTnI levels lead to a higher risk of stroke.

Abstract TMP99: Genetics Of Stroke Of Undetermined Source: Overlap With Known Stroke Etiologies And Associations With Modifiable Risk Factors

Introduction: Stroke etiology remains unknown in 30% of cases, hindering secondary prevention efforts. We leveraged human genetic data in order to identify evidence of overlap between stroke of undetermined source and defined stroke etiologies as well as causal relationships with modifiable risk factors. Methods: We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls from the NINDS Stroke Genetics Network with TOAST- and CCS-defined subtypes. Using genetic risk scores for large artery, cardioembolic, and small vessel stroke (LAS, CES, SVS) we assessed the degree of overlap with stroke of undetermined source and used pairwise GWAS to search for shared loci. We then applied Mendelian randomization (MR) to identify causal risk factors for stroke of undetermined source. Results: There was significant overlap between stroke of undetermined source and all defined stroke subtypes at a genome-wide and locus level (19 shared loci with LAS, 2 with CES, 5 with SVS). Shared loci pointed to altered gene expression in arterial tissue and blood and atherosclerosis-related mechanisms. Further, genetically predicted carotid intima media thickness was associated with stroke of undetermined source. While genetic liability to atrial fibrillation also showed a significant association, this was attenuated in analyses excluding cases with incomplete diagnostic workup. MR analyses showed significant associations in blood pressure, diabetes, waist-to-hip ratio, inflammatory pathways (IL-6 signaling, MCP-1 levels), and elevated factor XI levels with stroke of undetermined source (Figure). Conclusion: These analyses suggest that stroke of undetermined source shares genetic and modifiable risk factors with defined stroke subtypes. Together, they raise the hypothesis that refinement of current subtyping approaches can reduce the proportion of cases classified as undetermined and optimize secondary prevention strategies.

Abstract TMP115: Increased Expression Of Cd38 In Activated Astrocytes Contributes To Impaired Synaptic Plasticity Following Middle Cerebral Artery Occlusion

Introduction: Emerging evidence has implicated post-stroke cognitive impairment (PSCI) as a major contributor to long-term disability following acute ischemic stroke. While the hippocampus is shown to contribute to PSCI, the exact mechanisms underlying PSCI have yet to be elucidated. Interestingly, a preclinical model of large artery stroke (middle cerebral artery occlusion; MCAO) causes hippocampal dysfunction, despite direct ischemic insult to brain regions distant from the hippocampus, suggesting the injury causes perturbations in neural circuits. Thus, we utilize electrophysiological recordings of hippocampal LTP as an indicator of network health following ischemia. We hypothesize activated astrocytes in the hippocampus following MCAO increase expression of the ectoenzyme, CD38, which signals to neurons to impair plasticity. Methods: Extracellular field recordings of CA1 neurons were performed in acute hippocampal slices prepared 30 days after recovery from MCAO in adult (8-12 week) mice. Immunohistochemistry was performed to assess hippocampal CD38 expression and astrogliosis. Acute slices were treated with CD38 inhibitors (78c &amp; apigenin) to assess plasticity. Results: Recordings obtained in brain slices 30 days after MCAO exhibited a significant reduction in LTP; 161±9%, n=6 in sham compared to 115±4%, n=7 30 days after MCAO, in both ipsilateral and contralateral hippocampi. Immunohistochemical (IHC) staining indicates CD38 levels are increased and colocalize with activated astrocyte marker, GFAP, 30 days following MCAO. Bath application of CD38 inhibitors, 78c (vehicle n=6, 4.0±8.5% vs. 100nM 78c n=6, 78.3±15.8%; p&lt;0.05) and apigenin (vehicle n=7, 23.9±7% vs. 10μM apigenin n=7, 65.5±2.5%; p&lt;0.05), restored LTP in MCAO brain slices 30 days following injury. Conclusion: These data indicate that MCAO provides a reproducible model of post-stroke memory dysfunction (PSCI) and that remote astrogliosis in the uninjured hippocampus may contribute to altered neuronal function (plasticity). Our data implicates increased levels of CD38 impair plasticity following stroke. Therefore, reducing CD38 activity at chronic timepoints following ischemia may represent a novel strategy to treat the symptoms of PSCI.

Parkinson's Disease and Ischemic Stroke: a Bidirectional Mendelian Randomization Study.

We aimed to assess the potential causal association between Parkinson's disease (PD) and ischemic stroke (IS) with Mendelian randomization methods. Summary statistics data from two large-scale genome-wide association studies (GWAS) for 33,674 PD cases and 40,585 IS cases were used in this study. We used inverse variance-weighted method for primary analysis, and four other Mendelian randomization methods (weighted median, MR-Egger regression methods, robust adjusted profile score, radial regression) to test whether PD was causal for IS and its subtypes. Analyses were bidirectional to assess reverse causality. Primary analysis showed PD had a significantly causal association with IS (OR 1.04; 95% CI, 1.02-1.07; p = 0.0019), and two subtypes of IS, cardioembolic stroke (OR 1.11; 95% CI, 1.06-1.18; p = 0.0001) and large artery stroke (OR 1.08; 95% CI, 1.01-1.15; p = 0.034), but not with small-vessel stroke (p = 0.180). The point estimates from sensitivity analyses were in the same direction. There was no strong evidence for a reverse causal association between PD and IS. Using multiple Mendelian randomization methods based on large-scale GWAS, PD is a potential cause of cardioembolic stroke and large artery stroke, but not small-vessel stroke. Ischemic stroke does not cause PD.

Genetically Predicted Cardiac Troponin I Concentrations and Risk of Stroke and Atrial Fibrillation

ObjectivesObservational studies have shown that elevated circulating cardiac troponin I (cTnI) concentrations were linked to higher risk of stroke and atrial fibrillation, but the causality remains unclear. Therefore, we used mendelian randomization to assess the potential causal effects of cTnI concentrations on the risk of stroke, its subtypes and atrial fibrillation. Materials and methodsThe instrumental variables for circulating cTnI concentrations were selected from a genome-wide association study meta-analysis of 48,115 European individuals. We examined the associations of circulating cTnI concentrations with stroke, ischemic stroke, ischemic stroke subtypes (cardioembolic, large artery, small vessel stroke), intracerebral hemorrhage and atrial fibrillation. ResultsGenetically predicted elevated circulating cTnI concentrations were associated with higher risk of cardioembolic stroke (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.20–2.68; P = 0.004), but not associated with large artery stroke, small vessel stroke, total stroke, ischemic stroke and intracerebral hemorrhage. Additionally, we also found that elevated cTnI concentrations were causally linked to higher risk of atrial fibrillation (OR, 1.30; 95% CI, 1.10–1.53; P = 0.003). ConclusionsThis study provides evidence that genetically predicted circulating cTnI concentrations are causally linked to higher risk of cardioembolic stroke and atrial fibrillation.

Cardiac Risk Factors for Stroke: A Comprehensive Mendelian Randomization Study.

Observational studies suggest an association of stroke with cardiac traits beyond atrial fibrillation, the leading source of cardioembolism. However, controversy remains regarding a causal role of these traits in stroke pathogenesis. Here, we leveraged genetic data to systematically assess associations between cardiac traits and stroke risk using a Mendelian Randomization framework. We studied 66 cardiac traits including cardiovascular diseases, magnetic resonance imaging-derived cardiac imaging, echocardiographic imaging, and electrocardiographic measures, as well as blood biomarkers in a 2-sample Mendelian Randomization approach. Genetic predisposition to each trait was explored for associations with risk of stroke and stroke subtypes in data from the MEGASTROKE consortium (40 585 cases/406 111 controls). Using multivariable Mendelian Randomization, we adjusted for potential pleiotropic or mediating effects relating to atrial fibrillation, coronary artery disease, and systolic blood pressure. As expected, we observed strong independent associations between genetic predisposition to atrial fibrillation and cardioembolic stroke and between genetic predisposition to coronary artery disease as a proxy for atherosclerosis and large-artery stroke. Our data-driven analyses further indicated associations of genetic predisposition to both heart failure and lower resting heart rate with stroke. However, these associations were explained by atrial fibrillation, coronary artery disease, and systolic blood pressure in multivariable analyses. Genetically predicted P-wave terminal force in V1, an electrocardiographic marker for atrial cardiopathy, was inversely associated with large-artery stroke. Available genetic data do not support substantial effects of cardiac traits on the risk of stroke beyond known clinical risk factors. Our findings highlight the need to carefully control for confounding and other potential biases in studies examining candidate cardiac risk factors for stroke.

Migraine and Ischemic Stroke: A Mendelian Randomization Study.

Introduction Previous epidemiological studies have found an increased risk for ischemic stroke in patients with migraine; however, the evidence for a causal relationship between migraine and ischemic stroke is scarce. This study aims to explore the potential causal relationship between migraine and ischemic stroke and its subtypes [including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES)].MethodsWe used data on genetic variants associated with migraine identified from a genome-wide association study (GWAS) meta-analysis among 889,018 European ancestries. Summary data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium including up to 438,847 participants. We performed two-sample Mendelian randomization (MR) analyses using the inverse-variance-weighted method as the primary approach. The MR-Egger, weighted median, simple median, simple mode, and weighted mode methods were also conducted as sensitivity analyses to determine the robustness of our results.ResultsWe failed to detect statistically significant associations between migraine and ischemic stroke (OR, 0.935; 95% CI 0.851–1.027; P = 0.159) and its subtypes (LAS: OR, 0.818; 95% CI 0.692–0.967; P = 0.018) (SVS: OR, 0.935; 95% CI 0.781–1.119; P = 0.460) (CES: OR, 1.015; 95% CI 0.867–1.189; P = 0.850). The results were consistent with the sensitivity analyses.ConclusionsBy conducting a series of causal inference approaches, this study supports no causal effect of migraine on ischemic stroke and its subtypes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00310-y.

Stroke and Myocardial Infarction: A Bidirectional Mendelian Randomization Study.

BackgroundStroke and myocardial infarction (MI) are associated with each other, as demonstrated in observational studies. However, it is unclear whether this relationship is causal, and the purpose of this study was to explore the bidirectional causality between stroke and MI.MethodsCausality between stroke and MI was assessed using two-sample Mendelian randomization (MR). All genetic instruments related to stroke (40,585 cases; 406,111 controls) and MI (43,676 cases; 128,199 controls) were derived from large published genome-wide association study. The MR analysis was calculated with inverse-variance weighting, MR-Egger, weighted mode, weighted median, and simple mode methods, and sensitivity analyses are used to detect the heterogeneity or pleiotropy.ResultsGenetically predicted large-artery stroke (LAS) was causally related to higher odds of MI (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.06–1.20, p = 1.0×10−4), and the causal effect of LAS on MI was significantly weakened (OR = 1.09, 95% CI: 1.02–1.17, p = 0.017) after excluding the multipotent single-nucleotide polymorphisms (SNPs). MI phenotypes were genetically correlated with all ischemic strokes (OR = 1.15, 95% CI: 1.03–1.28, p = 0.013) and LAS (OR = 1.39, 95% CI: 1.14–1.71, p = 0.001); but a causal effect of MI on all ischemic strokes (OR = 1.00, 95% CI: 0.95–1.28, p = 0.219) and LAS (OR = 1.26, 95% CI: 0.93–1.69, p = 0.130) was not observed after excluding the multipotent SNPs.ConclusionThis MR analysis provides evidence to support the causal effect of LAS subtype on MI, and some factors act as confiding factors whereas others may act as mediators.

Deciphering the Irregular Risk of Stroke Increased by Obesity Classes: A Stratified Mendelian Randomization Study

BackgroundTo investigate the relationship between different classes of obesity and stroke, we conducted a stratified Mendelian randomization (MR) study.MethodsThe body mass index (BMI) data of 263,407 Europeans with three classes of obesity (obesity class I, 30 kg/m2 ≤ BMI < 35 kg/m2; obesity class II, 35 kg/m2 ≤ BMI < 40 kg/m2; obesity class III, 40 kg/m2 ≤ BMI) were extracted from the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary-level data of stroke and its subtypes [ischemic stroke (IS) and intracerebral hemorrhage (ICH)] were obtained from the genome-wide association study (GWAS) meta-analysis, which was performed by the MEGASTROKE consortium. MR methods were used to identify the causal relationships.ResultsThe MR analysis revealed that both obesity class I [odds ratio (OR) = 1.08, 95% CI: 1.05–1.12, p = 1.0 × 10-5] and obesity class II (OR = 1.06, 95% CI: 1.03–1.09, p = 1 × 10-4) were significantly positively related to IS, while obesity class III was not (OR = 1.01, 95% CI: 0.96–1.06, p = 0.65). In contrast to IS, there was no class of obesity associated with ICH risk. Further examination of the relationship between obesity classification and IS subtypes revealed that certain degrees of obesity were related to large artery stroke (LAS) (OR = 1.14, 95% CI: 1.04–1.24, p = 2.8 × 10-3 for class I; OR = 1.08, 95% CI: 1.01–1.16, p = 0.002 for class II) and cardioembolic stroke (CES) (OR = 1.11, 95% CI: 1.02–1.20, p = 0.02 for class I; OR = 1.08, 95% CI: 1.02–1.15, p = 0.007 for class II).ConclusionsA higher risk of IS, but not ICH, could be linked to obesity classes I and II. A strong association between LAS and CES and obesity was observed among all IS subtypes in the obese population.

Interactions Between Kidney Function and Cerebrovascular Disease: Vessel Pathology That Fires Together Wires Together.

The kidney and the brain, as high-flow end organs relying on autoregulatory mechanisms, have unique anatomic and physiological hemodynamic properties. Similarly, the two organs share a common pattern of microvascular dysfunction as a result of aging and exposure to vascular risk factors (e.g., hypertension, diabetes and smoking) and therefore progress in parallel into a systemic condition known as small vessel disease (SVD). Many epidemiological studies have shown that even mild renal dysfunction is robustly associated with acute and chronic forms of cerebrovascular disease. Beyond ischemic SVD, kidney impairment increases the risk of acute cerebrovascular events related to different underlying pathologies, notably large artery stroke and intracerebral hemorrhage. Other chronic cerebral manifestations of SVD are variably associated with kidney disease. Observational data have suggested the hypothesis that kidney function influences cerebrovascular disease independently and adjunctively to the effect of known vascular risk factors, which affect both renal and cerebral microvasculature. In addition to confirming this independent association, recent large-scale human genetic studies have contributed to disentangling potentially causal associations from shared genetic predisposition and resolving the uncertainty around the direction of causality between kidney and cerebrovascular disease. Accelerated atherosclerosis, impaired cerebral autoregulation, remodeling of the cerebral vasculature, chronic inflammation and endothelial dysfunction can be proposed to explain the additive mechanisms through which renal dysfunction leads to cerebral SVD and other cerebrovascular events. Genetic epidemiology also can help identify new pathological pathways which wire kidney dysfunction and cerebral vascular pathology together. The need for identifying additional pathological mechanisms underlying kidney and cerebrovascular disease is attested to by the limited effect of current therapeutic options in preventing cerebrovascular disease in patients with kidney impairment.

Genetic predisposition to Parkinson's disease and risk of cardio and cerebrovascular disease: a Mendelian randomization study

BackgroundObservational studies suggest that Parkinson's disease (PD) is related with the risk of cardio and cerebrovascular disease. However, the causality is not yet fully established. Therefore, we employed Mendelian randomization to assess whether PD is related to risk of ischemic stroke (IS), IS subtypes, coronary artery disease (CAD) and myocardial infarction (MI). MethodsEighty-eight and eleven single nucleotide polymorphisms associated with PD at the genome-wide significance level, were used as instrumental variables for PD in European and East Asian population respectively. Using a 2-sample MR, we examined associations with IS, IS related subtypes, CAD and MI in European population. We also assessed the causal association of PD with IS and CAD in East Asian population. The primary MR analyses were performed by using the random-effects inverse variance weighted approach. ResultsIn European population, genetic predisposition to PD was related to higher risk of IS (odds ratio [OR], 1.03 per doubling in odds of PD; 95% confidence interval [CI], 1.01–1.05; P = 0.002) and cardioembolic stroke (OR, 1.08 per doubling in odds of PD; 95% CI, 1.04–1.12; P = 1.29 × 10−4), but not large artery stroke, small vessel stroke, CAD and MI. In East Asian population, we found no evidence of causal effect of PD on the risk of IS and CAD. ConclusionsThis study found that genetic predisposition to PD is related to higher risk of IS and cardioembolic stroke in European population.

Childhood Obesity and Risk of Stroke: A Mendelian Randomisation Analysis.

Background: The causal relationship between childhood obesity and stroke remains unclear. Our objective was to elucidate the causal relationship between childhood obesity and the risk of stroke and its subtypes by performing Mendelian randomisation (MR) analyses. Methods: Genetic instruments for childhood obesity were obtained from a genome-wide association study (GWAS) of 13,848 European participants. Summary level data for stroke, intracerebral haemorrhage, ischaemic stroke (IS), and its subtypes were evaluated using the MEGASTROKE GWAS dataset, which included 446,696 European adults. Inverse-variance weighting, weighted-median analysis, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO), and MR-Robust Adjusted Profile Score were applied in this MR analysis. The leave-one-out sensitivity test, MR-PRESSO Global test, and Cochran’s Q test were conducted to confirm the accuracy and robustness of our results. Results: Genetic evaluations revealed that childhood obesity was associated with a higher risk of stroke (OR = 1.04, 95%CI: 1.01–1.07, p = 0.005) and IS (OR = 1.05, 95%CI: 1.02–1.08, p = 0.003), but not with intracerebral haemorrhage (ICH, OR = 0.93, 95%CI: 0.80–1.09, p = 0.39). In the subtype analysis, childhood obesity was also associated with large artery stroke (LAS, OR = 1.12, 95%CI: 1.02–1.22, p = 0.016) but not with cardioembolic stroke (OR = 1.06, 95%CI: 0.96–1.18, p = 0.21) and small vessel stroke (OR = 1.06, 95%CI: 0.98–1.15, p = 0.17). These results were stable in the sensitivity analysis and remained significant after Bonferroni correction. Conclusion: Our study provides evidence that childhood obesity is associated with a higher risk of stroke, IS, and LAS. The prevention of stroke, especially IS and LAS, should be promoted in populations with childhood obesity.

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&lt;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&lt;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 &lt; 50 years). PRI-PRS was also associated in GEOS (p&lt;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 9674: Stroke, Migraine, and Cervical Arterial Dissection: Shared Genetics Reveals Concordant and Opposing Risk Mechanisms

Introduction: Migraine, stroke, and cervical artery dissection (CeAD) represent a triad of cerebrovascular disorders with pairwise comorbid relationships and vascular involvement. Systematic exploration of their shared genetics may inform shared and divergent etiology. Methods: The largest available GWASs for all three disorders were used, including for subtypes of stroke (ischemic stroke [IS], large artery stroke [LAS], small vessel stroke [SVS], cardioembolic stroke [CE]) and migraine (with aura [MA] and without aura [MO]). For each pair of disorders, genetic correlation was assessed both on a genome-wide basis and within candidate loci for each disorder. Cross-trait meta-analysis was used to identify shared novel candidate loci. Causality of migraine susceptibility on stroke and CeAD was evaluated by Mendelian randomization (MR). Results: Among all pairs of disorders, genome-wide genetic correlation was only observed for CeAD and migraine, particularly MO. Local genetic correlations were more extensive between migraine and CeAD than migraine and stroke or CeAD and stroke, identifying novel CeAD associations at rs6693567 ( ADAMTSL4/ECM1 ), rs11187838 ( PLCE1 ), and rs7940646 ( MRVI1 ), while strengthening prior subthreshold evidence at rs9486725 ( FHL5 ) and rs650724 ( LRP1 ). At known migraine loci, novel associations with stroke had concordant risk alleles for SVS at rs191602009 ( CARF ), and for CE at rs55884259 ( NKX2-5 ). However, at other migraine loci, there were novel associations with opposite risk alleles for all stroke, IS, and SVS at rs55928386 ( HTRA1 ), for LAS at rs11172113 ( LRP1 ), and for all stroke and IS, respectively, at rs1535791 and rs4942561 (both LRCH1 ). rs182923402 (near PTCH1 ) was a novel locus for both migraine and CE with concordant effects. MR supported causal influence of migraine on CeAD (OR [95%CI] per doubling migraine prevalence=1.69 [1.24-2.3], p=0.0009) with concordant risk, but with opposite risk on LAS (0.86 [0.76 - 0.96], p=0.0067). Conclusions: Genetic effects between migraine and CeAD had concordant effects on risk, highlighting vascular functions in migraine and novel CeAD loci. Most shared loci for migraine and stroke subtypes had opposite effects on risk. The LRP1 locus was common to all three disorders.

Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies.

Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. These dysfunctions reflect defects that appear to be inherited and secondary to environmental exposures, including vascular risk factors. Interrogation in preclinical models shows consistent and converging molecular and cellular interactions across the endothelial-glial-neural unit that increasingly explain the human macroscopic observations and identify common patterns of pathology despite different triggers. Importantly, these insights may offer new targets for therapeutic intervention focused on restoring endothelial-glial physiology.

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&amp;lt;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.

The impact of plasma vitamin C levels on the risk of cardiovascular diseases and Alzheimer's disease: A Mendelian randomization study

Previous observational studies have reported associations between plasma vitamin C levels, and cardiovascular diseases (CVDs) and Alzheimer's disease (AD); however, no conclusive results have been obtained. We conducted a Mendelian randomization (MR) study to investigate the causality of vitamin C on the risk of nine CVDs [including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), stroke, ischemic stroke (IS), and IS subtypes] and Alzheimer's disease. Eleven single-nucleotide polymorphisms (SNPs) identified in a recent genome-wide meta-analysis (N=52,018) were used as the instrumental variables for plasma vitamin C levels. The summary-level data for CVDs and AD were extracted from consortia and genome-wide association studies (GWAS). We performed MR analyses using the fixed-effects inverse-variance-weighted (IVW) method, weighted median, and MR-Egger approaches. This MR study found suggestive evidence that genetic liability to higher vitamin C levels was associated with a lower risk of cardioembolic stroke [odds ratio (OR, presented per 1 standard deviation increase in plasma vitamin C levels)=0.773; 95% confidence interval (CI), 0.623-0.959; P=0.020] and AD (OR=0.968; 95% CI, 0.946-0.991; P=0.007) using the fixed-effects IVW method. Sensitivity analysis yielded directionally similar results. A null-association was observed between vitamin C and the other CVDs. Our MR study provided suggestive evidence that higher vitamin C levels were casually associated with a decreased risk of cardioembolic stroke and AD. No evidence was observed to suggest that vitamin C affected the risk of CAD, MI, AF, HF, stroke, IS, large artery stroke, or small vessel stroke. However, well-designed studies are warranted to confirm these results and determine the underlying mechanisms of the causal links.

Estonian young stroke registry: High burden of risk factors and high prevalence of cardiomebolic and large-artery stroke.

The aim of the present study was to assess the risk factor burden and stroke etiology of young stroke patients in Estonia and to compare the results with similar cohorts from other countries. This study includes ischemic stroke patients aged 18-54years from the prospective Estonian Young Stroke Registry between 2013 and 2020. All patients were managed in a stroke unit following a prespecified detailed protocol. Data on stroke risk factors, etiology, and stroke severity were analyzed. A total of 437 patients (mean age 44.7 ± 8.3years; 62% males) were included in the registry during the 8-year study period. A total of 50.2% of patients had ≥ 3 well-documented risk factors (higher for men: odds ratio (OR) 3.8; 95% cardiac index confidence interval (CI) 1.8-8.3; p < .001) and 6.2% of patients had ≥ 3 less well-documented risk factors. While 42% of patients had undetermined cause of stroke (34% of them cryptogenic), the second most frequent etiologies were large-artery atherosclerosis and cardioembolism (both 19%). 60 percent of cardioembolic strokes were due to high-risk causes. Large-artery atherosclerosis was more prevalent in men (OR 1.8; 95% CI 1-3.3; p = .05) and among older patients (OR 6.2; 95% CI 1.8-21.4; p = .008). The median National Institutes of Health Stroke Scale score on admission was 3 (interquartile ranges 2-6), stroke was more severe in men (p = .05). Our study revealed that young patients with stroke in Estonia have higher burden of well-documented risk factors, higher prevalence of high-risk cardioembolic causes and higher prevalence of large-artery stroke compared to other young stroke cohorts.

Daytime sleepiness and risk of stroke: A Mendelian randomization analysis

ObjectiveDaytime sleepiness is known to be related to stroke, but whether daytime sleepiness is a risk factor for stroke remains unclear. We conducted a two-sample Mendelian randomization study to assess the relationship between daytime sleepiness and stroke, ischemic stroke (IS) and IS subtypes. MethodsThirty-six single-nucleotide polymorphisms (SNPs) associated with daytime sleepiness were selected as instrumental variables, which were identified from a recent genome-wide association study(N = 452,071). Summary statistics of the SNPs on stroke, IS and IS subtypes were derived from the MEGASTROKE consortium with 40,585 stroke cases and 406,111 controls. ResultsWe found that daytime sleepiness was associated with large artery stroke (OR, 6.75; 95%CI, 1.49–30.57; p = 0.013), but not with all stroke (OR, 1.29; 95%CI, 0.81–2.05; p = 0.282), all ischemic stroke(OR, 1.46; 95%CI, 0.90–2.39; p = 0.136), cardioembolic stroke(OR, 1.0; 95%CI, 0.39–2.64; p = 0.984), or small artery stroke(OR, 1.52; 95%CI, 0.46–5.05; p = 0.485). ConclusionOur findings indicated that daytime sleepiness is causally associated with an increased risk of large artery stroke. Further studies are necessary to verify our results and explain the physiological mechanisms.