Article

Stroke Genetics Network (SiGN) Study Design and Rationale for a Genome-Wide Association Study of Ischemic Stroke Subtypes

September 2013
Stroke 44(10)

September 2013
44(10)

DOI:10.1161/STROKEAHA.113.001857

Source
PubMed

Authors:

Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10 296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14 549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

Anti-Müllerian Hormone and Cardiometabolic Disease in Women: A Two-Sample Mendelian Randomization Study

Article

Full-text available

Jul 2022

Background: Higher age-specific circulating anti-Müllerian hormone (AMH) levels have been linked to a lower risk of cardiometabolic outcomes. However, whether AMH has a casual role in the etiology of these diseases is unknown. The objective of this study was therefore to explore if circulating AMH levels have a causal effect on risk of coronary artery disease (CAD), ischemic stroke and type 2 diabetes (T2D) in women, using a two-sample Mendelian randomization (MR) approach. Methods: We used four single nucleotide polymorphisms (SNPs) from the most recent AMH GWAS meta-analysis as instrumental variables. Summary-level data for CAD (n = 149,752; 11,802 cases), ischemic stroke (n = 17,541; 4678 cases) and T2D (n = 464,389; 30,052 cases) were extracted from the UK Biobank, the Stroke Genetics Network, and DIAMANTE consortia, respectively. To assess the presence of potential pleiotropy we tested the association of the four AMH SNPs, both individually and combined in a weighted genetic risk score, with a range of cardiovascular risk factors and intermediate traits using UK Biobank data. Results: MR estimates, i.e., inverse variance-weighted odds ratios (ORIVW), did not support a causal effect of circulating AMH levels on CAD (ORIVW = 1.13, 95% CI: 0.95–1.35), ischemic stroke (ORIVW = 1.11, 95% CI: 0.83–1.49), and T2D (ORIVW = 0.98, 95% CI: 0.87–1.10). After adjustment for multiple testing, we observed associations between genetically predicted AMH and age at menopause, and age at menarche, but not with intermediate traits on the causal pathway between AMH and cardiometabolic health, such as atherosclerosis or glucose levels. Conclusions: This study does not provide evidence for a causal effect of circulating AMH levels on CAD, ischemic stroke and T2D in women, although weak instrument bias cannot be excluded.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study

Article

Full-text available

Mar 2020
J NEUROL

Petrea Frid

Objective Posterior circulation ischemic stroke (PCiS) constitutes 20–30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. Methods Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. Results PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04–1.61; male sex, OR = 1.46; 95% CI 1.21–1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. Conclusion Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Big Data Approaches to Phenotyping Acute Ischemic Stroke Using Automated Lesion Segmentation of Multi-Center Magnetic Resonance Imaging Data

Article

Full-text available

Jun 2019

Background and Purpose— We evaluated deep learning algorithms’ segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods— Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms’ performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results— The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P <0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm ³ (0.9–16.6 cm ³ ). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P <0.0001) and different topography compared with other stroke subtypes. Conclusions— Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.

The Protease-Activated Receptor 4 Ala120Thr Variant Alters Platelet Responsiveness to Low-Dose Thrombin, Protease-Activated Receptor 4 Desensitization and Is Blocked by Noncompetitive P2Y 12 Inhibition

Article

Full-text available

Oct 2018
J THROMB HAEMOST

Background F2RL3 encodes protease‐activated receptor 4 (PAR4) and harbors an A/G SNP (rs773902) with racially dimorphic allelic frequencies. This SNP mediates an alanine to threonine substitution at residue 120 that alters platelet PAR4 activation by the artificial PAR4‐activation peptide, AYPGKF. Objectives We determined the functional effect of rs773902 on stimulation by a physiological agonist, thrombin, and on antiplatelet antagonist activity. Methods Healthy human donors were screened and genotyped for rs773902. Platelet function was assessed in response to thrombin without and with antiplatelet antagonists. The association of rs773902 alleles with stroke was assessed in the Stroke Genetics Network study. Results Compared to rs773902 GG donors, platelets from rs773902 AA donors had increased aggregation to subnanomolar concentrations of thrombin, increased granule secretion and decreased sensitivity to PAR4 desensitization. In the presence of PAR1 blockade, this genotype effect was abolished by higher concentrations of or longer exposure to thrombin. We were unable to detect a genotype effect on thrombin‐induced PAR4 cleavage, dimerization, and lipid raft localization; however, rs773902 AA platelets required 3‐fold higher PAR4‐AP for receptor desensitization. Ticagrelor, but not vorapaxar, abolished the PAR4 variant effect on thrombin‐induced platelet aggregation. A significant association of modest effect was detected between the rs773902 A allele and stroke. Conclusion The F2RL3 rs773902 SNP alters platelet reactivity to thrombin; the allelic effect requires P2Y12, and is not affected by gender. Ticagrelor blocks the enhanced reactivity of rs773902 A platelets. PAR4 encoded by the rs773902 A allele is relatively resistant to desensitization and may contribute to stroke risk. This article is protected by copyright. All rights reserved.

Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke

Article

Oct 2017
BRAIN

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

Genetic Susceptibility to Cerebrovascular Disease

Article

Apr 2016

Purpose of review: Cerebrovascular disease (CeVD) remains a major cause of death and a leading cause of disability worldwide. CeVD is a complex and multifactorial disease caused by the interaction of vascular risk factors, environment, and genetic factors. In the present article, we discussed genetic susceptibility to CeVD, with particular emphasis on genetic studies of the associations between lipid traits and CeVD. Recent findings: Several animal and clinical studies clearly defined genetic predisposition to atherosclerosis and CeVD, and particularly to ischemic stroke. Recent evidence has shown that traditional vascular risk factors explain only a small proportion of variance in atherosclerosis, suggesting that additional nontraditional factors and novel genetic determinants impact CeVD. With the help of genome-wide technology, novel genetic variants have been implicated in CeVD and lipid metabolism such as those in protein convertase subtilisin/kexin type 9 (PCSK9) gene in stroke and familial hypercholesterolemia. These studies are important as they contribute to our understanding of the genetic mechanisms underlying CeVD and to developing more effective CeVD prevention strategies. Summary: CeVD is a complex and multifactorial disease and genetics likely plays an important role in its pathogenesis. The gene-gene and gene-environment interactions of genes involved in biology of vascular disease, including the lipid metabolism are important factors for individual susceptibility to CeVD. Accounting for individual variation in genes, environment and lifestyle will bring us closer to precision medicine, which is an emerging and recently introduced new approach for disease treatment and prevention in clinical practice.

loci associated with ischemic stroke (SiGN): a genome-wide association study

Article

Dec 2015

Background The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identifi cation of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.

Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study

Article

Dec 2015
LANCET NEUROL

Background: The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. Methods: To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. Findings: We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10(-8); joint OR 1·19, 1·12-1·26, p=1·30 × 10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10(-19); joint OR 1·37, 1·30-1·45, p=2·79 × 10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10(-7); joint OR 1·17, 1·11-1·23, p=2·29 × 10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10(-8); joint OR 1·24, 1·15-1·33, p=4·52 × 10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10(-8); joint OR 1·17, 1·11-1·23, p=2·92 × 10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. Interpretation: Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. Funding: US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Evidence of survival bias in the association between APOE-Є4 and age of ischemic stroke onset

Preprint

Full-text available

Dec 2023

Large genome-wide association studies (GWAS) employing case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing age at onset (AAO) of ischemic stroke. Analyses were conducted in a Discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value < 1×10 ⁻⁵ in a sex-combined or sex-stratified analysis using summary data from two additional replication cohorts. In the women-only meta-analysis, we detected significant evidence for association of AAO with rs429358, an exonic variant in APOE that encodes for the APOE-є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29 years earlier stroke AOO (meta p-value = 2.48×10 ⁻¹¹ ). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decline in mortality among APOE-є4 carriers and have no association to stroke AAO per se. Using a simulation study, we found that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a two-fold increase on mortality risk would lead to an observed effect of AAO that is comparable to what we found. In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.

Evaluation of Density-Based Spatial Clustering for Identifying Genomic Loci Associated with Ischemic Stroke in Genome-Wide Data

Article

Full-text available

Oct 2023
INT J MOL SCI

The genetic architecture of ischemic stroke (IS), which is one of the leading causes of death worldwide, is complex and underexplored. The traditional approach for associative gene mapping is genome-wide association studies (GWASs), testing individual single-nucleotide polymorphisms (SNPs) across the genomes of case and control groups. The purpose of this research is to develop an alternative approach in which groups of SNPs are examined rather than individual ones. We proposed, validated and applied to real data a new workflow consisting of three key stages: grouping SNPs in clusters, inferring the haplotypes in the clusters and testing haplotypes for the association with phenotype. To group SNPs, we applied the clustering algorithms DBSCAN and HDBSCAN to linkage disequilibrium (LD) matrices, representing pairwise r 2 values between all genotyped SNPs. These clustering algorithms have never before been applied to genotype data as part of the workflow of associative studies. In total, 883,908 SNPs and insertion/deletion polymorphisms from people of European ancestry (4929 cases and 652 controls) were processed. The subsequent testing for frequencies of haplotypes restored in the clusters of SNPs revealed dozens of genes associated with IS and suggested the complex role that protocadherin molecules play in IS. The developed workflow was validated with the use of a simulated dataset of similar ancestry and the same sample sizes. The results of classic GWASs are also provided and discussed. The considered clustering algorithms can be applied to genotypic data to identify the genomic loci associated with different qualitative traits, using the workflow presented in this research.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women

Article

Full-text available

Nov 2022
HUM BRAIN MAPP

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome

Article

Jul 2022

Objective To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. Methods MR neuroimaging and National Institutes of Health Stroke Scale data at index stroke, as well as modified Rankin Scale (mRS) at 3-6 months post-stroke were obtained from the MRI-GENIE study of acute ischemic stroke (AIS) patients. Individual WMH volume was automatically derived from FLAIR-images. Stroke lesions were automatically segmented from DWI-images, parcellated into atlas-defined brain regions and further condensed to ten lesion patterns via machine-learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS>2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high versus low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age ² , sex, total DWI-lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. Results A total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8(14.5), 40% women), 698 patients to long-term functional outcome analyses (age: 65.9(14.7), 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left-hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular and inferior frontal regions and lesions affecting right-hemispheric temporo-parietal regions had more pronounced effects on stroke severity in case of high compared to low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific WMH effects on stroke severity, higher WMH burden increased the odds of unfavorable outcomes independent of lesion location. Conclusions Higher WMH burden may be associated with an increased stroke severity in case of stroke lesions involving left-hemispheric insular, opercular and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporo-parietal regions (potentially linked to attention). Our findings suggest that patients with specific constellations of WMH burden and lesion locations may have greater benefits from acute recanalization treatments. Future clinical studies are warranted to systematically assess this assumption and guide more tailored treatment decisions.

Sex-specific lesion pattern of functional outcomes after stroke

Article

Full-text available

Feb 2022

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.

Stroke Genomics: Current Knowledge, Clinical Applications and Future Possibilities

Article

Full-text available

Feb 2022
BSRCCS

The pathophysiology of stoke involves many complex pathways and risk factors. Though there are several ongoing studies on stroke, treatment options are limited, and the prevalence of stroke is continuing to increase. Understanding the genomic variants and biological pathways associated with stroke could offer novel therapeutic alternatives in terms of drug targets and receptor modulations for newer treatment methods. It is challenging to identify individual causative mutations in a single gene because many alleles are responsible for minor effects. Therefore, multiple factorial analyses using single nucleotide polymorphisms (SNPs) could be used to gain new insight by identifying potential genetic risk factors. There are many studies, such as Genome-Wide Association Studies (GWAS) and Phenome-Wide Association Studies (PheWAS) which have identified numerous independent loci associated with stroke, which could be instrumental in developing newer drug targets and novel therapies. Additionally, using analytical techniques, such as meta-analysis and Mendelian randomization could help in evaluating stroke risk factors and determining treatment priorities. Combining SNPs into polygenic risk scores and lifestyle risk factors could detect stroke risk at a very young age and help in administering preventive interventions.

Fine-Mapping of the PLCL2 Gene Identifies Candidate Variants Associated With Ischaemic Stroke Risk in Metabolic Syndrome Patients

Article

Full-text available

Jan 2022

A genome-wide association study (GWAS) reported PLCL2 on chromosome 3p24. 3 (rs4618210:A>G) as a novel susceptibility locus for myocardial infarction in the Japanese population. As the most common pathological process, atherosclerosis leads to metabolic syndrome (MetS)-related ischaemic stroke (IS) and myocardial infarction. Hypothesizing that polymorphisms of the PLCL2 gene might be associated with the onset and prognosis of IS in MetS patients, we performed the following study in a Chinese Han population. A total of 709 cases (patients with MetS plus IS) and 711 controls (patients with MetS) were enrolled. A fine-mapping strategy was adopted to identify tagged single nucleotide polymorphisms (SNPs) of the PLCL2 gene, and improved multiplex ligation detection reaction (iMLDR) technology was used to genotype the selected SNPs. Logistic regression was used to analyse the values of the selected SNPs for the risk of IS between the cases and controls, adjusting for sex, age, hypertension, dyslipidaemia, hyperglycaemia, smoking and drinking. To compare the mean age of IS onset among different risk score groups, a genetic risk score was constructed for each case. The cumulative risk of IS events in the case group was presented using a cumulative incidence curve. All cases were followed up for 3 months, and functional outcomes were recorded prospectively. Two SNPs (rs4685423 and rs4618210) were significantly related to the risk of IS in MetS patients. For rs4685423, patients who were AA homozygotes were less likely to suffer from IS than C-allele carriers (OR 0.718; 95% CI 0.567–0.909; multivariate-adjusted, P = 0.006). For rs4618210, A-allele carriers were less likely to develop IS than patients who were GG homozygotes (OR 0.679; 95% CI 0.548–0.841; multivariate-adjusted, P < 0.001). As the genetic risk score increased, the mean age at IS onset decreased (log-rank P = 0.010). There was no statistically significant difference in the distribution of the 90-day modified Rankin Scale (mRS) outcomes across the rs4685423 (P = 0.319) or rs4618210 polymorphisms (P = 0.148). Our findings suggested that genetic polymorphisms of PLCL2 might be associated with the onset of MetS-related IS. Further studies are warranted to validate our findings in other ethnic populations.

Hypernet-Ensemble Learning of Segmentation Probability for Medical Image Segmentation with Ambiguous Labels

Preprint

Full-text available

Dec 2021

Despite the superior performance of Deep Learning (DL) on numerous segmentation tasks, the DL-based approaches are notoriously overconfident about their prediction with highly polarized label probability. This is often not desirable for many applications with the inherent label ambiguity even in human annotations. This challenge has been addressed by leveraging multiple annotations per image and the segmentation uncertainty. However, multiple per-image annotations are often not available in a real-world application and the uncertainty does not provide full control on segmentation results to users. In this paper, we propose novel methods to improve the segmentation probability estimation without sacrificing performance in a real-world scenario that we have only one ambiguous annotation per image. We marginalize the estimated segmentation probability maps of networks that are encouraged to under-/over-segment with the varying Tversky loss without penalizing balanced segmentation. Moreover, we propose a unified hypernetwork ensemble method to alleviate the computational burden of training multiple networks. Our approaches successfully estimated the segmentation probability maps that reflected the underlying structures and provided the intuitive control on segmentation for the challenging 3D medical image segmentation. Although the main focus of our proposed methods is not to improve the binary segmentation performance, our approaches marginally outperformed the state-of-the-arts. The codes are available at \url{https://github.com/sh4174/HypernetEnsemble}.

Lesions in putative language and attention regions are linked to more severe strokes in patients with higher white matter hyperintensity burden

Preprint

Full-text available

Nov 2021

Objective To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. Methods MR neuroimaging and National Institutes of Health Stroke Scale data at index stroke, as well as modified Rankin Scale (mRS) at 3-6 months post-stroke were obtained from MRI-GENIE study of acute ischemic stroke (AIS) patients. Individual WMH volume was automatically derived from FLAIR-images. Stroke lesions were automatically segmented from DWI-images, spatially normalized and parcellated into atlas-defined brain regions. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS>2) were modeled within a purpose-built machine learning and Bayesian regression framework. In particular, interaction effects between stroke lesions and a high versus low WMH burden were integrated via hierarchical model structures. Models were adjusted for the covariates age, age2, sex, total DWI-lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. Results A total of 928 AIS patients contributed to stroke severity analyses (mean age: 64.8(14.5), 40% women), 698 patients to functional outcome analyses (mean age: 65.9(14.7), 41% women). Individual stroke lesions were represented in five anatomically distinct left-hemispheric and five right-hemispheric lesion patterns. Across all patients, acute stroke severity was substantially explained by three of these patterns, that were particularly focused on bilateral subcortical and left-hemispherically pronounced cortical regions. In high WMH burden patients, two lesion patterns consistently emerged as more pronounced in case of stroke severity: the first pattern was centered on left-hemispheric insular, opercular and inferior frontal regions, while the second pattern combined right-hemispheric temporo-parietal regions. Bilateral subcortical regions were most relevant in explaining long term unfavorable outcome. No WMH-specific lesion patterns of functional outcomes were substantiated. However, a higher overall WMH burden was associated with higher odds of unfavorable outcomes. Conclusions Higher WMH burden increases stroke severity in case of stroke lesions involving left-hemispheric insular, opercular and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporo-parietal regions (potentially linked to attention). These findings may contribute to augment stroke outcome predictions and motivate a WMH burden and stroke lesion pattern-specific clinical management of AIS patients.

Excessive White Matter Hyperintensity Increases Susceptibility to Poor Functional Outcomes After Acute Ischemic Stroke

Article

Full-text available

Sep 2021

Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to−6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.

A survey of functional dyspepsia in 361,360 individuals: Phenotypic and genetic cross‐disease analyses

Article

Full-text available

Aug 2021
NEUROGASTROENT MOTIL

Background Functional dyspepsia (FD) is a common gastrointestinal condition of poorly understood pathophysiology. While symptoms’ overlap with other conditions may indicate common pathogenetic mechanisms, genetic predisposition is suspected but has not been adequately investigated. Methods Using healthcare, questionnaire, and genetic data from three large population‐based biobanks (UK Biobank, EGCUT, and MGI), we surveyed FD comorbidities, heritability, and genetic correlations across a wide spectrum of conditions and traits in 10,078 cases and 351,282 non‐FD controls of European ancestry. Key Results In UK Biobank, 281 diagnoses were detected at increased prevalence in FD, based on healthcare records. Among these, gastrointestinal conditions (OR = 4.0, p < 1.0 × 10⁻³⁰⁰), anxiety disorders (OR = 2.3, p < 1.4 × 10⁻²⁷), ischemic heart disease (OR = 2.2, p < 2.3 × 10⁻⁷⁶), and infectious and parasitic diseases (OR = 2.1, p = 1.5 × 10⁻⁷³) showed strongest association with FD. Similar results were obtained in an analysis of self‐reported conditions and use of medications from questionnaire data. Based on a genome‐wide association meta‐analysis of genotypes across all cohorts, FD heritability was estimated close to 5% (hSNP2 = 0.047, p = 0.014). Genetic correlations indicate FD predisposition is shared with several other diseases and traits (rg > 0.344), mostly overlapping with those also enriched in FD patients. Suggestive (p < 5.0 × 10⁻⁶) association with FD risk was detected for 13 loci, with 2 showing nominal replication (p < 0.05) in an independent cohort of 192 FD patients. Conclusions & Inferences FD has a weak heritable component that shows commonalities with multiple conditions across a wide spectrum of pathophysiological domains. This new knowledge contributes to a better understanding of FD etiology and may have implications for improving its treatment.

Fine-Mapping of the PLCL2 Gene Identifies Candidate Variants Associated With Ischaemic Stroke Risk in Metabolic Syndrome Patients

Preprint

Full-text available

Jan 2021

Background and aims A genome-wide association study (GWAS) reported PLCL2 on chromosome 3p24.3 (rs4618210:A>G) as a novel susceptibility locus for myocardial infarction in the Japanese population. As the most common pathological process, atherosclerosis leads to metabolic syndrome (MetS)-related ischaemic stroke (IS) and myocardial infarction. Hypothesizing that polymorphisms of the PLCL2 gene might be associated with the onset and prognosis of IS in MetS patients, we performed the following study in a Chinese Han population. Methods A total of 709 cases (patients with MetS plus IS) and 711 controls (patients with MetS) were enrolled. A fine-mapping strategy was adopted to identify tagged single nucleotide polymorphisms (SNPs) of the PLCL2 gene, and improved multiplex ligation detection reaction (iMLDR) technology was used to genotype the selected SNPs. Logistic regression was used to analyse the values of the selected SNPs for the risk of IS between the cases and controls, adjusting for sex, age, hypertension, dyslipidaemia, hyperglycaemia, smoking and drinking. To compare the mean age of IS onset among different risk score groups, a genetic risk score was constructed for each case. The cumulative risk of IS events in the case group was presented using a cumulative incidence curve. All cases were followed up for 3 months, and functional outcomes were recorded prospectively. Results Two SNPs (rs4685423 and rs4618210) were significantly related to the risk of IS in MetS patients. For rs4685423, patients who were AA homozygotes were less likely to suffer from IS than C-allele carriers (OR 0.718; 95% CI 0.567–0.909; multivariate-adjusted, P = 0.006). For rs4618210, A-allele carriers were less likely to develop IS than patients who were GG homozygotes (OR 0.679; 95% CI 0.548–0.841; multivariate-adjusted, P < 0.001). As the genetic risk score increased, the mean age at IS onset decreased (log-rank P = 0.010). There was no statistically significant difference in the distribution of the 90-day modified Rankin Scale (mRS) outcomes across the rs4685423 (P = 0.319) or rs4618210 polymorphisms (P = 0.148). Conclusions Our findings suggested that genetic polymorphisms of PLCL2 might be associated with the onset of MetS-related IS. Further studies are warranted to validate our findings in other ethnic populations.

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

Article

Full-text available

Jun 2020

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.

White matter hyperintensity burden in acute stroke patients differs by ischemic stroke subtype

Article

Jun 2020

Objective To examine etiologic stroke subtypes and vascular risk factor profiles and their association with white matter hyperintensity (WMH) burden in patients hospitalized for acute ischemic stroke (AIS). Methods For the MRI Genetics Interface Exploration (MRI-GENIE) study, we systematically assembled brain imaging and phenotypic data for 3,301 patients with AIS. All cases underwent standardized web tool–based stroke subtyping with the Causative Classification of Ischemic Stroke (CCS). WMH volume (WMHv) was measured on T2 brain MRI scans of 2,529 patients with a fully automated deep-learning trained algorithm. Univariable and multivariable linear mixed-effects modeling was carried out to investigate the relationship of vascular risk factors with WMHv and CCS subtypes. Results Patients with AIS with large artery atherosclerosis, major cardioembolic stroke, small artery occlusion (SAO), other, and undetermined causes of AIS differed significantly in their vascular risk factor profile (all p < 0.001). Median WMHv in all patients with AIS was 5.86 cm ³ (interquartile range 2.18–14.61 cm ³ ) and differed significantly across CCS subtypes ( p < 0.0001). In multivariable analysis, age, hypertension, prior stroke, smoking (all p < 0.001), and diabetes mellitus ( p = 0.041) were independent predictors of WMHv. When adjusted for confounders, patients with SAO had significantly higher WMHv compared to those with all other stroke subtypes ( p < 0.001). Conclusion In this international multicenter, hospital-based cohort of patients with AIS, we demonstrate that vascular risk factor profiles and extent of WMH burden differ by CCS subtype, with the highest lesion burden detected in patients with SAO. These findings further support the small vessel hypothesis of WMH lesions detected on brain MRI of patients with ischemic stroke.

Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke

Article

Full-text available

Feb 2020

Ischemic stroke (IS), caused by obstruction of cerebral blood flow, is one of the leading causes of death. While neurologists agree on delineation of IS into three subtypes (cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS)), several subtyping systems exist. The most commonly used systems are TOAST (Trial of Org 10172 in Acute Stroke Treatment) and CCS (Causative Classification System for Stroke), but agreement is only moderate. We have compared two approaches to combining the existing subtyping systems for a phenotype suited for a genome-wide association study (GWAS). We used the NINDS Stroke Genetics Network dataset (SiGN, 11,477 cases with CCS and TOAST subtypes and 28,026 controls). We defined two new phenotypes: the intersect, for which an individual must be assigned the same subtype by CCS and TOAST; and the union, for which an individual must be assigned a subtype by either CCS or TOAST. The union yields the largest sample size while the intersect yields a phenotype with less potential misclassification. We performed GWAS for all subtypes, using the original subtyping systems, the intersect, and the union as phenotypes. In each subtype, heritability was higher for the intersect compared with the other phenotypes. We observed stronger effects at known IS variants with the intersect compared with the other phenotypes. With the intersect, we identify rs10029218:G>A as an associated variant with SVS. We conclude that this approach increases the likelihood to detect genetic associations in ischemic stroke.

Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome

Article

Apr 2018
GASTROENTEROLOGY

Background & aims: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. Methods: We studied 7,287,191 high-quality single-nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; m=9576) compared to the remainder of the cohort (controls; n=336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n=249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories, to obtain biological insights from the observed associations. Results: We identified a genome-wide significant association on chromosome 9q31.2 (SNP rs10512344; P=3.57×10-8), in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P<5.0×10-6). Sex-stratified analyses revealed that the variants at 9q32.1 affect risk of IBS in only women (P=4.29×10-10in UK Biobank) and also associate with constipation-predominant IBS in women (P=.015 in the tertiary cohort) and harder stools in women (P=.0012 in the population-based sample). Functional annotation of the 9q32.1 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. Conclusions: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q32.1 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

Polygenic Risk for Depression Increases Risk of Ischemic Stroke: From the Stroke Genetics Network Study

Article

Full-text available

Feb 2018

Background and purpose: Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis. Methods: We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 43 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses. Results: The depression PRS was associated with higher risk of ischemic stroke overall in both European (P=0.025) and African ancestry (P=0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00-1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04-1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons. Conclusions: Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry.

Joinville stroke biobank: Study protocol and first year’s results

Article

Full-text available

Dec 2017
ARQ NEURO-PSIQUIAT

Methods: Blood samples were collected from patients included in the Joinville Stroke Registry and four Brazilian cities. Demographic socio-economic data, cardiovascular risk factors, Causative Classification System for Ischemic Stroke, Trial of Org 10172 in Acute Stroke Treatment and National Institutes of Health scores, functional stroke status (modified Rankin) and brain images were recorded. Additionally, controls from both geographic regions were recruited. High-molecular-weight genomic DNA was obtained from all participants. Results: A total of 2,688 patients and 3,282 controls were included. Among the patients, 76% had ischemic stroke, 12% transient ischemic attacks, 9% hemorrhagic stroke and 3% subarachnoid hemorrhage. Patients with undetermined ischemic stroke were most common according the Trial of Org 10172 in Acute Stroke Treatment (40%) and Causative Classification System for Ischemic Stroke (47%) criteria. A quarter of the patients were under 55 years of age at the first-ever episode. Conclusions: We established the Joinville Stroke Biobank and discuss its potential for contributing to the understanding of the risk factors leading to stroke.

Design and rationale for examining neuroimaging genetics in ischemic stroke: The MRI-GENIE study

Article

Full-text available

Oct 2017

Objective: To describe the design and rationale for the genetic analysis of acute and chronic cerebrovascular neuroimaging phenotypes detected on clinical MRI in patients with acute ischemic stroke (AIS) within the scope of the MRI-GENetics Interface Exploration (MRI-GENIE) study. Methods: MRI-GENIE capitalizes on the existing infrastructure of the Stroke Genetics Network (SiGN). In total, 12 international SiGN sites contributed MRIs of 3,301 patients with AIS. Detailed clinical phenotyping with the web-based Causative Classification of Stroke (CCS) system and genome-wide genotyping data were available for all participants. Neuroimaging analyses include the manual and automated assessments of established MRI markers. A high-throughput MRI analysis pipeline for the automated assessment of cerebrovascular lesions on clinical scans will be developed in a subset of scans for both acute and chronic lesions, validated against gold standard, and applied to all available scans. The extracted neuroimaging phenotypes will improve characterization of acute and chronic cerebrovascular lesions in ischemic stroke, including CCS subtypes, and their effect on functional outcomes after stroke. Moreover, genetic testing will uncover variants associated with acute and chronic MRI manifestations of cerebrovascular disease. Conclusions: The MRI-GENIE study aims to develop, validate, and distribute the MRI analysis platform for scans acquired as part of clinical care for patients with AIS, which will lead to (1) novel genetic discoveries in ischemic stroke, (2) strategies for personalized stroke risk assessment, and (3) personalized stroke outcome assessment.

Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes: Mendelian randomization study

Article

Aug 2017

\textbf{Objective:}$ To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes. $\textbf{Methods:}$ MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNP-stroke associations were derived from METASTROKE and the Stroke Genetics Network (n = 18,476 ischemic stroke cases and 37,296 controls). $\textbf{Results:}$ Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16-1.40, p = 3.3 × 10(-7)) and small vessel stroke (OR 1.21, 95% CI 1.10-1.33, p = 8.9 × 10(-5)) but not cardioembolic stroke (OR 1.06, 95% CI 0.97-1.15, p = 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype. $\textbf{Conclusions:}$ This study provides support that T2D may be causally associated with large artery stroke.

Blood Biomarkers in Minor Stroke and Transient Ischemic Attack

Article

Jun 2016

Minor stroke and transient ischemic attack (TIA) are common disorders with a high rate of subsequent disabling stroke, so the early recognition and management of minor stroke and TIA is of great importance. At the moment, the diagnosis of these disorders is based on neurologic deficits in a stroke-clinician’s examination of the patient, supplemented by the results of acute brain imaging. However, high variability in TIA diagnosis has been reported between physicians, even trained vascular neurologists, and image-based diagnostic confirmation is not always readily available. Some patients still have ischemic events despite sustained standard secondary preventive therapy. Blood biomarkers are promising to aid in the diagnosis, risk stratification, and individual treatment of minor stroke and TIA. Some studies are being conducted in this field. This mini-review aims to highlight potential biomarkers for diagnosis and those helpful in predicting the risk of future stroke and the selection of treatment.

The Washington University Central Neuroimaging Data Archive

Article

Oct 2015
NEUROIMAGE

Since the early 2000's, much of the neuroimaging work at Washington University (WU) has been facilitated by the Central Neuroimaging Data Archive (CNDA), an XNAT-based imaging informatics system. The CNDA is uniquely related to XNAT, as it served as the original codebase for the XNAT open source platform. The CNDA hosts data acquired in over 1000 research studies, encompassing 36,000 subjects and more than 60,000 imaging sessions. Most imaging modalities used in modern human research are represented in the CNDA, including magnetic resonance (MR), positron emission tomography (PET), computed tomography (CT), nuclear medicine (NM), computed radiography (CR), digital radiography (DX), and ultrasound (US). However, the majority of the imaging data in the CNDA are MR and PET of the human brain. Currently, about 20% of the total imaging data in the CNDA is available by request to external researchers. CNDA's available data includes large sets of imaging sessions and in some cases clinical, psychometric, tissue, or genetic data acquired in the study of Alzheimer's disease, brain metabolism, cancer, HIV, sickle cell anemia, and Tourette syndrome.

Multi-Omics Approaches to Discovering Acute Stroke Injury and Recovery Mechanisms

Chapter

Apr 2024

Millions of people suffer an acute stroke each year, resulting in an enormous global burden of residual disability and mortality. Despite decades of work to discover effective therapeutics to prevent the consequences of ischemic injury and promote recovery, there have been hundreds of failed clinical trials. Genetics and other omics offer the opportunity to apply ‘reverse translational’ approaches to discover mechanisms important to mitigating injury and promoting recovery. In this chapter, we present a rationale and outline methodology for this broad investigative approach, including the development of creative endophenotypes and integration of multi-omic bioinformatics, as means of enhancing the discovery pathway. We also discuss the urgent need to expand collaborations and harness emerging technologies such as artificial intelligence to phenotype large enough cohorts to have adequate power to find genes and pathways relevant to stroke outcomes. Finally, we discuss challenges and future directions in this rapidly expanding area of stroke research.

A pilot genome-wide association study meta-analysis of gastroparesis

Article

Full-text available

Sep 2023

Background: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction. Objective: Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed. Methods: We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene-set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls. Results: While no SNP associations were detected at strict significance (p ≤ 5 × 10-8 ), nine independent genomic loci were associated at suggestive significance (p ≤ 1 × 10-5 ), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 × 10-7 ) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein-coding candidate genes. Gene-set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR ≤ 0.05). The GP risk allele rs6984536A (Peroxidasin-Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls). Conclusion: We report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory-motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.

Clinical and Genetic Atrial Fibrillation Risk and Discrimination of Cardioembolic From Noncardioembolic Stroke

Article

Jun 2023
STROKE

Background: Stroke is a leading cause of death and disability worldwide. Atrial fibrillation (AF) is a common cause of stroke but may not be detectable at the time of stroke. We hypothesized that an AF polygenic risk score (PRS) can discriminate between cardioembolic stroke and noncardioembolic strokes. Methods: We evaluated AF and stroke risk in 26 145 individuals of European descent from the Stroke Genetics Network case-control study. AF genetic risk was estimated using 3 recently developed PRS methods (LDpred-funct-inf, sBayesR, and PRS-CS) and 2 previously validated PRSs. We performed logistic regression of each AF PRS on AF status and separately cardioembolic stroke, adjusting for clinical risk score (CRS), imputation group, and principal components. We calculated model discrimination of AF and cardioembolic stroke using the concordance statistic (c-statistic) and compared c-statistics using 2000-iteration bootstrapping. We also assessed reclassification of cardioembolic stroke with the addition of PRS to either CRS or a modified CHA2DS2-VASc score alone. Results: Each AF PRS was significantly associated with AF and with cardioembolic stroke after adjustment for CRS. Addition of each AF PRS significantly improved discrimination as compared with CRS alone (P<0.01). When combined with the CRS, both PRS-CS and LDpred scores discriminated both AF and cardioembolic stroke (c-statistic 0.84 for AF; 0.74 for cardioembolic stroke) better than 3 other PRS scores (P<0.01). Using PRS-CS PRS and CRS in combination resulted in more appropriate reclassification of stroke events as compared with CRS alone (event reclassification [net reclassification indices]+=14% [95% CI, 10%-18%]; nonevent reclassification [net reclassification indices]-=17% [95% CI, 15%-0.19%]) or the modified CHA2DS2-VASc score (net reclassification indices+=11% [95% CI, 7%-15%]; net reclassification indices-=14% [95% CI, 12%-16%]) alone. Conclusions: Addition of polygenic risk of AF to clinical risk factors modestly improves the discrimination of cardioembolic from noncardioembolic strokes, as well as reclassification of stroke subtype. Polygenic risk of AF may be a useful biomarker for identifying strokes caused by AF.

Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics

Article

Full-text available

Aug 2022

Background purpose A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. Materials and methods Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. Results We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL. Conclusion Multiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.

Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke

Article

Aug 2022
J Stroke Cerebrovasc Dis

Objective To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. Methods Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. Results Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01–0.03) and decreased risk of ACiS (p=0.010–0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008–0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001–0.010) and migraine without aura (p=0.032–0.048). Migraine with aura PRS did not show a differential association in our analyses. Conclusions Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Shared genetic background between SARS-CoV-2 infection and large artery stroke

Article

Apr 2022

Background and aims: Increased risk of stroke, particularly large artery stroke (LAS), has been observed in patients with COVID-19. The biological processes underlying the observed higher risk are still unknown. We explored the association between stroke subtypes and COVID-19 susceptibility to understand whether biological mechanisms specific to SARS-CoV-2 uptake/infection could be leading to excess stroke risk in this population. Patients and methods: We constructed a polygenic risk score (PRS) of COVID-19 susceptibility and tested its association with stroke subtypes using individual- and summary-level genetic data (SiGN, MEGASTROKE). We generated co-expression networks of genes involved in SARS-CoV-2 uptake/infection (ACE2, TMPRSS2, BEST3, ISLR2 and ADAM17) based on existing tissue expression libraries. Gene-based association testing was performed using S PrediXcan and VEGAS2. Permutation independence tests were performed to assess SARS CoV-2-related gene enrichment in stroke and its subtypes. Results: Our PRS demonstrated an association between COVID-19 susceptibility and LAS in SiGN (OR=1.05 per SD increase, 95% CI: [1.00, 1.10], p=0.04) and MEGASTROKE (β=0.510, 95% CI: [0.242, 0.779], FDR-p = 0.0019). The SARS-CoV-2 risk-related ISLR2 co-expression gene network was significantly associated with genetic risk of LAS in aorta, tibial arteries, and multiple brain regions (P < 0.05). Conclusion: Presence of genetic correlation and significant pathway enrichment suggest that increases in LAS risk reported in COVID-19 patients may be intrinsic to the viral infection, rather than a more generalized response to severe illness. Data access statement: The data and the code that support the findings of this study are available from the authors upon reasonable request.

Diagnostic and Prognostic Blood Biomarkers in Transient Ischemic Attack and Minor Ischemic Stroke: An Up-To-Date Narrative Review

Article

Mar 2022
J Stroke Cerebrovasc Dis

Introduction Early diagnosis and correct risk stratification in patients with transient ischemic attack (TIA) and minor ischemic stroke (MIS) is crucial for the high rate of subsequent disabling stroke. Although highly improved, diagnosis and prognostication of TIA/MIS patients remain still based on clinical and neuroimaging findings, with some inter-rater variability even among trained neurologists. Objectives To provide an up-to-date overview of diagnostic and prognostic blood biomarkers in TIA and MIS patients. Material and methods We performed a bibliographic search on PubMed database with last access on July 10th 2021. More than 680 articles were screened and we finally included only primary studies on blood biomarkers. Results In a narrative fashion, we discussed about blood biomarkers investigated in TIA/MIS patients, including inflammatory, thrombosis, neuronal injury and cardiac analytes, antibodies and microRNAs. Other soluble molecules have been demonstrated to predict the risk of recurrent cerebrovascular events or treatment response in these patients. A rapid point of care assay, combining the determination of different biomarkers, has been developed to improve triage recognition of acute cerebrovascular accidents. Conclusions The implementation of blood biomarkers in the clinical management of TIA/MIS could ameliorate urgent identification, risk stratification and individual treatment choice. Large prospective and longitudinal studies, adopting standardized sampling and analytic procedures, are needed to clarify blood biomarkers kinetic and their relationship with TIA and minor stroke etiology.

Fetal posterior cerebral artery configurations in an ischemic stroke versus an unselected hospital population

Article

Full-text available

Nov 2021

Background: Few MRA-based studies have systematically evaluated the prevalence and laterality of a fetal configuration of the posterior cerebral artery (FTP) in ischemic stroke populations versus other populations. This common variant is important in the setting of acute stroke and secondary prevention decisions. Objective: To determine the prevalence and laterality of FTP configurations in MRI-DWI verified acute ischemic stroke patients investigated with MRA, and compare the findings with an unselected hospital population investigated with computed tomography angiography (CTA). We also evaluated the association of FTP with posterior cerebral artery (PCA) territory infarctions. Methods: We reviewed the MRAs of 1407 ischemic stroke patients with acute lesions on MRI-DWI sequences and 546 consecutive CTAs of patients investigated on any indication in a tertiary hospital. The MRA and CTA assessments were made by neuroradiologists blinded to original reports on stroke location and vessel anatomy. Results: The prevalence of any FTP was similar in ischemic stroke patients (31%) and unselected patients (32%). Unilateral FTP was significantly more frequent on the right than on the left side in both groups (15% right vs. 8% left). The presence of FTP ipsilateral to stroke side was not associated with involvement of the PCA territory versus no FTP on the stroke side. Conclusions: FTP is present in approximately 30% of ischemic stroke patients and unselected hospital populations and was detected significantly more frequently on the right versus left side in both groups. PCA territory infarction was not associated with the presence of ipsilateral FTP.

The copy number variation and stroke (CaNVAS) risk and outcome study

Article

Full-text available

Apr 2021
PLOS ONE

Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.

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

Article

Jul 2020

Background and purpose: 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. Methods: 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. Results: 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. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

Association Between the Polymorphism of Aldehyde Dehydrogenase 2 Gene and Cerebral Infarction in a Hakka Population in Southern China

Article

Full-text available

Apr 2020
BIOCHEM GENET

Genetic factors play an important role in determining the susceptibility to ischemic stroke. Herein, we examined the association of an aldehyde dehydrogenase 2 (ALDH2) gene polymorphism with cerebral infarction. Patients with cerebral infarction (n = 963) and healthy controls (n = 921) were included. Genotyping was performed using gene chip platform analysis, and Sanger sequencing was used to confirm ALDH2 genotypes. The risk prediction of ALDH2 polymorphisms for cerebral infarction was examined under three genetic modes of inheritance. For males, ALDH2*2/*2 genotype was a significant risk factor for cerebral infarction in the co-dominant model (age-, smoking-, and drinking-adjusted OR 1.514, 95% CI 1.005–2.282, p = 0.047) and the recessive model (age-, smoking-, and drinking-adjusted OR 1.601, 95% CI 1.078–2.379, p = 0.020). However, for females, ALDH2*2/*2 genotype was a protective factor for cerebral infarction in the co-dominant model (age-, smoking-, and drinking-adjusted OR 0.450 95% CI 0.215–0.941, p = 0.034) and the recessive model (age-, smoking-, and drinking-adjusted OR 0.440, 95% CI 0.214–0.903, p = 0.025). Further, logistic regression analysis revealed that age, smoking, hypertension, hyperlipidemia, and hypercholesterolemia were significant risks for the presence of cerebral infarction. In conclusion, these findings support an association of ALDH2 gene polymorphisms with ischemic stroke in a Chinese Hakka population. In particular, homozygote ALDH2*2/*2 may be a risk factor for cerebral infarction in males, but contribute to reduced risk for cerebral infarction in females.

Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke

Preprint

Full-text available

Jul 2019

Stroke causes approximately 1 in every 20 deaths in the United States. Most strokes are ischemic, caused by a blockage of blood flow to the brain. While neurologists agree on the delineation of ischemic stroke (IS) into the three most common subtypes (cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS)), several different subtyping systems exist. The two most commonly-used clinical subtyping systems are TOAST (Trial of Org 10172 in Acute Stroke Treatment) and CCS (Causative Classification System for Stroke), but agreement between these two systems is only moderate. Here, we have compared two approaches to combining the existing subtyping systems for a phenotype suited for a genome-wide association study (GWAS). We used the NINDS Stroke Genetics Network dataset (SiGN, 13,390 cases and 28,026 controls), which includes cases with both CCS and TOAST subtypes. We defined two new phenotypes: 1) the intersect, for which an individual must be assigned the same subtype by CCS and TOAST; and 2) the union, for which an individual must be assigned a subtype by either CCS or TOAST. The union yields the largest sample size while the intersect may yield a phenotype with less potential misclassification. We performed GWAS for all subtypes, using the original subtyping systems, the intersect, and the union as phenotypes. In each subtype, heritability was higher for the intersect phenotype compared to the union, CCS (alone), and TOAST (alone) phenotypes. We observed stronger effects at known IS variants with the intersect compared to the other phenotype definitions. In GWAS of the intersect, we identify rs10029218 as an associated variant with small vessel stroke. We conclude that in the absence of a golden standard for phenotyping, taking this alternate approach yields more power to detect genetic associations in ischemic stroke. Author summary Around one in five people will have a stroke at some point in their life. Most strokes (~80%) are ischemic, caused by a blockage of blood supply to the brain. Ischemic stroke risk is partly influenced by lifestyle, and partly by genetics. There are different ischemic stroke subtypes, and genome-wide association studies (GWAS) indicate that the genetic risk for these subtypes is influenced by different genetic factors. Genetic studies of ischemic stroke are therefore typically performed by analyzing each subtype separately. There are several methods to determine someone’s subtype based on clinical features. To find more genetic factors that influence ischemic stroke risk, we aimed to find a group of patients that are phenotypically similar by using information from all subtyping methods. We compared a group of patients assigned the same subtype by all subtyping methods (the intersect) to a group of patients assigned that subtype by at least one subtyping method (the union). Even though the intersect sample size is smaller, we find genetic factors in the intersect GWAS have stronger genetic effects, likely explained by the fact that we are more certain of the subtype in the intersect. Using the intersect, we find new risk-associated genetic factors.

Genetic Study of White Matter Integrity in UK Biobank (N=8448) and the Overlap With Stroke, Depression, and Dementia

Article

Full-text available

May 2018

Background and purpose: Structural integrity of the white matter is a marker of cerebral small vessel disease, which is the major cause of vascular dementia and a quarter of all strokes. Genetic studies provide a way to obtain novel insights in the disease mechanism underlying cerebral small vessel disease. The aim was to identify common variants associated with microstructural integrity of the white matter and to elucidate the relationships of white matter structural integrity with stroke, major depressive disorder, and Alzheimer disease. Methods: This genome-wide association analysis included 8448 individuals from UK Biobank-a population-based cohort study that recruited individuals from across the United Kingdom between 2006 and 2010, aged 40 to 69 years. Microstructural integrity was measured as fractional anisotropy- (FA) and mean diffusivity (MD)-derived parameters on diffusion tensor images. White matter hyperintensity volumes (WMHV) were assessed on T2-weighted fluid-attenuated inversion recovery images. Results: We identified 1 novel locus at genome-wide significance (VCAN [versican]: rs13164785; P=3.7×10-18 for MD and rs67827860; P=1.3×10-14 for FA). LD score regression showed a significant genome-wide correlation between FA, MD, and WMHV (FA-WMHV rG 0.39 [SE, 0.15]; MD-WMHV rG 0.56 [SE, 0.19]). In polygenic risk score analysis, FA, MD, and WMHV were significantly associated with lacunar stroke, MD with major depressive disorder, and WMHV with Alzheimer disease. Conclusions: Genetic variants within the VCAN gene may play a role in the mechanisms underlying microstructural integrity of the white matter in the brain measured as FA and MD. Mechanisms underlying white matter alterations are shared with cerebrovascular disease, and inherited differences in white matter microstructure impact on Alzheimer disease and major depressive disorder.

Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes: Mendelian randomization study

Article

Jun 2017
NEUROLOGY

Objective: To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes. Methods: MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNP-stroke associations were derived from METASTROKE and the Stroke Genetics Network (n = 18,476 ischemic stroke cases and 37,296 controls). Results: Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16-1.40, p = 3.3 × 10(-7)) and small vessel stroke (OR 1.21, 95% CI 1.10-1.33, p = 8.9 × 10(-5)) but not cardioembolic stroke (OR 1.06, 95% CI 0.97-1.15, p = 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype. Conclusions: This study provides support that T2D may be causally associated with large artery stroke.

Pharmacogenetic Associations of ?1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes)

Article

Mar 2017
STROKE

Background and purpose: Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and ?-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by ?-blocker treatment in patients with a history of stroke. Methods: Nine hundred and twenty-six participants of the SPS3 trial's (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). Results: MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00-2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01-3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03-1.26) in SiGN. In SPS3, ?-blocker-treated Gly49 carriers had increased MACE versus non-?-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20-3.45). No associations were observed with the Arg389Gly polymorphism. Conclusion: Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among ?-blocker-treated individuals. Further research is needed to define ?-blocker benefit among ischemic stroke patients by ADRB1 genotype. Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Genetic, Clinical and Population Priors for Brain Images

Thesis

Full-text available

Aug 2016

Adrian V Dalca

We develop mathematical models that exploit external information to improve analysis of a medical scan. Medical images enable visualization of the human body, and are central in clinical practice and many large-scale scientific studies. Medical image analysis uses computational models to interpret these scans towards the clinical or research goals. For example, in this thesis we are motivated by a clinical study of ischemic stroke, which aims to quantify cerebrovascular disease burden as observed in medical scans, along with its population trends and genetic predisposition. In most analyses, anatomical information is extracted from images to provide insight into a problem, facilitating understanding of genetic variants, clinical variables and population trends. In contrast, this thesis investigates what these external factors tell us about the human anatomy and the medical scans themselves. First, we show how genetic and clinical indicators can be used to predict MRI scans of anatomical change through a semi-parametric generative model. Second, we demonstrate that a cohort of subjects with cerebrovascular disease can help identify the spatially complex pathology in a new subject through a generative computational model. Third, we use large collections of clinical images to dramatically improve the resolution of a new scan and recover fine-scale anatomy. We also present an approach for rapid interactive visualization of images in large studies. Bringing our methods together in large scale analyses of stroke and dementia subjects, we demonstrate new avenues of research enabled by these contributions.

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Article

Jun 2016
LANCET NEUROL

Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45.8 years to 76.4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 x10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 x10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1.08, 95% CI 1.05-1-12, p=1.48 x10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity a marker of cerebral small vessel disease in stroke-free adults (n=21079; p=0.0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (fox2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms.

A stroke of insight from genetics

Article

Jun 2016
LANCET NEUROL

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Article

Jun 2016
LANCET NEUROL

Background: Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods: For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings: We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation: We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding: NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

A stroke of insight from genetics

Article

Apr 2016
LANCET NEUROL

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Article

Full-text available

Sep 2012
Nat Genet

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10(-4); discovery and replication combined OR = 1.21, P = 4.7 × 10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

Disparities in Stroke Type and Vascular Risk Factors Between 2 Hispanic Populations in Miami and Mexico City

Article

Full-text available

Jun 2012
J Stroke Cerebrovasc Dis

Background: The heterogeneous nature and determinants of stroke among different Hispanic groups was examined by comparing hospitalized Hispanic stroke patients in Miami, where the Hispanic population is largely of Caribbean origin, to a Mestizo population in Mexico City. Methods: Consecutive Hispanic patients who were admitted with stroke or transient ischemic attack (TIA) and included in the prospective stroke registries of 2 tertiary care teaching hospitals were studied. Demographic factors, stroke subtypes, vascular risk factors, stroke severity, and outcomes were compared. Vascular risk factor definitions were standardized. Results: A total of 928 patients (520 Mexicans and 408 Miami Hispanics) were analyzed. Mexicans were younger, with a greater proportion of women. More cerebral venous thromboses (CVTs) were admitted in Mexico, while TIA and stroke mimics were more commonly admitted in Miami; cardioembolic strokes were more commonly ascertained in Miami, and more cryptogenic strokes in Mexico. Stroke severity was similar for intracerebral hemorrhages, but more severe ischemic strokes and CVTs were included in the Mexican registry. Outcome at 1 and 3 months was similar in both registries after adjusting for age and baseline stroke severity. After adjusting for age and sex, hypertension, dyslipidemia, and atrial fibrillation were more frequent, and diabetes mellitus was less frequent, among Miami Hispanics compared to Mexicans. Conclusions: We found significant differences in the frequency of hypertension, diabetes, dyslipidemia, and atrial fibrillation in Miami Hispanics and Mexican stroke patients, highlighting the heterogeneity of the Hispanic ethnic group. Future studies are needed to clarify the relative contribution of genetic and environmental disparities amongst Mexican and Caribbean Hispanic stroke patients.

A map of human genome variation from population-scale sequencing

Article

Full-text available

Oct 2010

Consortium, T.G.P.: A map of human genome variation from population-scale sequencing. Nature 467, 1061-1073

Article

Full-text available

Oct 2010
NATURE

The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10 g-8 per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research. © 2010 Macmillan Publishers Limited. All rights reserved.

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Article

Full-text available

Mar 2012
Nat Genet

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

The Extensible Neuroimaging Archive Toolkit - An informatics platform for managing, exploring, and sharing neuroimaging data

Article

Full-text available

Mar 2007
NEUROINFORMATICS

The Extensible Neuroimaging Archive Toolkit (XNAT) is a software platform designed to facilitate common management and productivity tasks for neuroimaging and associated data. In particular, XNAT enables qualitycontrol procedures and provides secure access to and storage of data. XNAT follows a threetiered architecture that includes a data archive, user interface, and middleware engine. Data can be entered into the archive as XML or through data entry forms. Newly added data are stored in a virtual quarantine until an authorized user has validated it. XNAT subsequently maintains a history profile to track all changes made to the managed data. User access to the archive is provided by a secure web application. The web application provides a number of quality control and productivity features, including data entry forms, data-type-specific searches, searches that combine across data types, detailed reports, and listings of experimental data, upload/download tools, access to standard laboratory workflows, and administration and security tools. XNAT also includes an online image viewer that supports a number of common neuroimaging formats, including DICOM and Analyze. The viewer can be extended to support additional formats and to generate custom displays. By managing data with XNAT, laboratories are prepared to better maintain the long-term integrity of their data, to explore emergent relations across data types, and to share their data with the broader neuroimaging community.

Disparities in Stroke Incidence Contributing to Disparities in Stroke Mortality

Article

Full-text available

Apr 2011
ANN NEUROL

While black-white and regional disparities in U.S. stroke mortality rates are well documented, the contribution of disparities in stroke incidence is unknown. We provide national estimates of stroke incidence by race and region, contrasting these to publicly available stroke mortality data. This analysis included 27,744 men and women without prevalent stroke (40.4% black), aged ≥45 years from the REasons for Geographic And Racial Differences in Stroke (REGARDS) national cohort study, enrolled 2003-2007. Incident stroke was defined as first occurrence of stroke over 4.4 years of follow-up. Age-sex-adjusted stroke mortality rates were calculated using data from the Centers for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiological Research (WONDER) System. There were 460 incident strokes over 113,469 person-years of follow-up. Relative to the rest of the United States, incidence rate ratios (IRRs) of stroke in the southeastern stroke belt and stroke buckle were 1.06 (95% confidence interval [CI], 0.87-1.29) and 1.19 (95% CI, 0.96-1.47), respectively. The age-sex-adjusted black/white IRR(black) was 1.51 (95% CI, 1.26-1.81), but for ages 45-54 years the IRR(black) was 4.02 (95% CI, 1.23-13.11) while for ages 85+ it was 0.86 (95% CI, 0.33-2.20). Generally, the IRRs(black) were less than the mortality rate ratios (MRRs) across age groups; however, only in ages 55-64 years and 65-74 years did the 95% CIs of IRRs(black) not include the MRR(black) . The MRRs for regions were within 95% CIs for IRRs. National patterns of black-white and regional differences in stroke incidence are similar to those for stroke mortality; however, the magnitude of differences in incidence appear smaller.

The Secondary Prevention of Small Subcortical Strokes (SPS3) Study

Article

Full-text available

Apr 2011
Int J Stroke

Small subcortical strokes, also known as lacunar strokes, comprise more than 25% of brain infarcts, and the underlying vasculopathy is the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in S3 patients is unclear. The aim of the Secondary Prevention of Small Subcortical Strokes study (Trial registration: NCT00059306) is to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events. Secondary Prevention of Small Subcortical Strokes is a randomised, multicentre clinical trial (n = 3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomised, in a 2 × 2 factorial design, to antiplatelet therapy--325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind--and to one of two levels of systolic blood pressure targets--'intensive' (<130 mmHg) vs. 'usual' (130-149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischaemic or haemorrhagic) is the primary outcome and will be analysed separately for each intervention. The secondary outcomes are the rate of cognitive decline and major vascular events. The primary and most secondary outcomes are adjudicated centrally by those unaware of treatment assignment. Secondary Prevention of Small Subcortical Strokes will address several important clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imaging-defined lacunar infarcts, which are likely due to small vessel disease. The results will inform the management of millions of patients with this common vascular disorder.

Bio-Repository of DNA in stroke (BRAINS): a study protocol

Article

Full-text available

Mar 2011
BMC MED GENET

Stroke is one of the commonest causes of mortality in the world and anticipated to be an increasing burden to the developing world. Stroke has a genetic basis and identifying those genes may not only help us define the mechanisms that cause stroke but also identify novel therapeutic targets. However, large scale highly phenotyped DNA repositories are required in order for this to be achieved. The proposed Bio-Repository of DNA in Stroke (BRAINS) will recruit all subtypes of stroke as well as controls from two different continents, Europe and Asia. Subjects recruited from the UK will include stroke patients of European ancestry as well as British South Asians. Stroke subjects from South Asia will be recruited from India and Sri Lanka. South Asian cases will also have control subjects recruited. We describe a study protocol to establish a large and highly characterized stroke biobank in those of European and South Asian descent. With different ethnic populations being recruited, BRAINS has the ability to compare and contrast genetic risk factors between those of differing ancestral descent as well as those who migrate into different environments.

The Stroke Data Bank: Design, methods, and baseline characteristics

Article

Full-text available

Jun 1988

The National Institute of Neurological and Communicative Disorders and Stroke initiated the Stroke Data Bank, which is a multicenter project to prospectively collect data on the clinical course and sequelae of stroke. Additional objectives were to provide information that would enable a standard diagnostic clinical evaluation, to identify prognostic factors, and to provide planning data for future studies. A brief description of the structure and methods precede the baseline characterization of 1,805 patients enrolled in the Stroke Data Bank between July 1983 and June 1986. Two thirds of these patients were admitted within 24 hours after stroke onset. Medical history, neurologic history, and hospitalization summaries are presented separately for the following stroke subtypes: infarction, unknown cause; embolism from cardiac source; infarction due to atherosclerosis; lacune; parenchymatous or intracerebral hemorrhage; subarachnoid hemorrhage; and other. The utility and limitations of these data are discussed.

The Siblings with Ischemic Stroke Study (SWISS) protocol

Article

Full-text available

Feb 2002
BMC MED GENET

Family history and twins studies suggest an inherited component to ischemic stroke risk. Candidate gene association studies have been performed but have limited capacity to identify novel risk factor genes. The Siblings With Ischemic Stroke Study (SWISS) aims to conduct a genome-wide scan in sibling pairs concordant or discordant for ischemic stroke to identify novel genetic risk factors through linkage analysis. Screening at multiple clinical centers identifies patients (probands) with radiographically confirmed ischemic stroke and a family history of at least 1 living full sibling with stroke. After giving informed consent, without violating privacy among other family members, the proband invites siblings concordant and discordant for stroke to participate. Siblings then contact the study coordinating center. The diagnosis of ischemic stroke in potentially concordant siblings is confirmed by systematic centralized review of medical records. The stroke-free status of potentially discordant siblings is confirmed by validated structured telephone interview. Blood samples for DNA analysis are taken from concordant sibling pairs and, if applicable, from 1 discordant sibling. Epstein-Barr virus-transformed lymphoblastoid cell lines are created, and a scan of the human genome is planned. Conducting adequately powered genomics studies of stroke in humans is challenging because of the heterogeneity of the stroke phenotype and the difficulty of obtaining DNA samples from clinically well-characterized members of a cohort of stroke pedigrees. The multicentered design of this study is intended to efficiently assemble a cohort of ischemic stroke pedigrees without invoking community consent or using cold-calling of pedigree members.

Ischemic Stroke Subtype Incidence Among Whites, Blacks, and Hispanics The Northern Manhattan Study

Article

Full-text available

Apr 2005
CIRCULATION

Stroke incidence is greater in blacks than in whites; data on Hispanics are limited. Comparing subtype-specific ischemic stroke incidence rates may help to explain race-ethnic differences in stroke risk. The aim of this population-based study was to determine ischemic stroke subtype incidence rates for whites, blacks, and Hispanics living in one community. A comprehensive stroke surveillance system incorporating multiple overlapping strategies was used to identify all cases of first ischemic stroke occurring between July 1, 1993, and June 30, 1997, in northern Manhattan. Ischemic stroke subtypes were determined according to a modified NINDS scheme, and age-adjusted, race-specific incidence rates calculated. The annual age-adjusted incidence of first ischemic stroke per 100,000 was 88 (95% CI, 75 to 101) in whites, 149 (95% CI, 132 to 165) in Hispanics, and 191 (95% CI, 160 to 221) in blacks. Among blacks compared with whites, the relative rate of intracranial atherosclerotic stroke was 5.85 (95% CI, 1.82 to 18.73); extracranial atherosclerotic stroke, 3.18 (95% CI, 1.42 to 7.13); lacunar stroke, 3.09 (95% CI, 1.86 to 5.11); and cardioembolic stroke, 1.58 (95% CI, 0.99 to 2.52). Among Hispanics compared with whites, the relative rate of intracranial atherosclerotic stroke was 5.00 (95% CI, 1.69 to 14.76); extracranial atherosclerotic stroke, 1.71 (95% CI, 0.80 to 3.63); lacunar stroke, 2.32 (95% CI, 1.48 to 3.63); and cardioembolic stroke, 1.42 (95% CI, 0.97 to 2.09). The high ischemic stroke incidence among blacks and Hispanics compared with whites is due to higher rates of all ischemic stroke subtypes.

Psychosocial Risk Factors and the Metabolic Syndrome in Elderly Persons: Findings From the Health, Aging and Body Composition Study

Article

Full-text available

Jun 2007

Psychosocial factors have been associated with metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. This study investigated the cross-sectional relationship between psychosocial risk factors and the metabolic syndrome in a community-based sample of older persons. Participants were 2917 persons aged 70-79 years enrolled in the Health, Aging and Body Composition study. Depressive and anxiety symptoms, negative life events, and inadequate emotional support were assessed, and a summary psychosocial risk index was calculated. Metabolic syndrome was defined as three or more of the following criteria: abdominal obesity, high triglycerides, low high-density lipoprotein (HDL) cholesterol, high fasting glucose, and high blood pressure. Negative life events and inadequate emotional support increased the odds of having metabolic syndrome after adjustment for demographic and lifestyle variables (odds ratio [OR] per life event = 1.13, 95% confidence interval [CI] = 1.05-1.22; OR = 1.35, 95% CI = 1.10-1.66, respectively). The relationship between depressive symptoms and metabolic syndrome was only found in white (OR per standard deviation [SD] = 1.11, 95% CI = 1.01-1.23), but not in black (OR per SD = 0.97, 95% CI = 0.86-1.11) persons. Anxiety symptoms were significantly associated with metabolic syndrome in men (OR per SD = 1.13, 95% CI = 1.00-1.28), but not in women (OR per SD = 0.98, 95% CI = 0.89-1.08). Moreover, a higher score on the psychosocial risk index was associated with an increased probability of having the metabolic syndrome (OR = 1.30, 95% CI = 1.12-1.52). In the elderly population, different psychosocial risk factors are associated with a higher prevalence of the metabolic syndrome. Whether reduction or better management of psychosocial risk factors can improve the metabolic profile remains to be demonstrated.

Juster FT, Suzman R. An overview of the health and retirement study. J Hum Res 40: S7-S56

Article

Jan 1995

This paper examines the scientific, public policy, and organizational background out of which the Health and Retirement Study emerged. It describes the evolution of the major parameters of the survey and the unique planning structure designed to ensure that the substantive insights of the research community were fully reflected in the content of the database, highlights key survey innovations contained in the HRS, and provides a preliminary assessment of the quality of the data as reflected by sample size, sample composition, response rate, and survey content. The paper also describes the several types of administrative data that are expected to be added to the HRS data: earnings and benefits from Social Security files, and health insurance and pension data from the employers of survey respondents.

An Overview of the Health and Retirement Study

Article

Jan 1995

Smoking and Genetic Risk Variation Across Populations of European, Asian, and African American Ancestry-A Meta-Analysis of Chromosome 15q25

Article

May 2012
GENET EPIDEMIOL

Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.

The Causative Classification of Stroke system: An international reliability and optimization study

Article

Oct 2010
NEUROLOGY

Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. The κ value for causative classification was 0.80 (95% confidence interval [CI] 0.78-0.81) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.70 (95% CI 0.69-0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: κ = 0.81 (95% CI 0.79-0.82) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.79 (95% CI 0.78-0.80) for the 16-subtype CCS. The κ value for phenotypic classification was 0.79 (95% CI 0.77-0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93-0.98) for cardioembolism, 0.88 (95% CI 0.85-0.91) for small artery occlusion, and 0.79 (0.76-0.82) for other uncommon causes. CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras.

Quality Control and Quality Assurance in Genotypic Data for Genome-Wide Association Studies

Article

Sep 2010
GENET EPIDEMIOL

Genome-wide scans of nucleotide variation in human subjects are providing an increasing number of replicated associations with complex disease traits. Most of the variants detected have small effects and, collectively, they account for a small fraction of the total genetic variance. Very large sample sizes are required to identify and validate findings. In this situation, even small sources of systematic or random error can cause spurious results or obscure real effects. The need for careful attention to data quality has been appreciated for some time in this field, and a number of strategies for quality control and quality assurance (QC/QA) have been developed. Here we extend these methods and describe a system of QC/QA for genotypic data in genome-wide association studies (GWAS). This system includes some new approaches that (1) combine analysis of allelic probe intensities and called genotypes to distinguish gender misidentification from sex chromosome aberrations, (2) detect autosomal chromosome aberrations that may affect genotype calling accuracy, (3) infer DNA sample quality from relatedness and allelic intensities, (4) use duplicate concordance to infer SNP quality, (5) detect genotyping artifacts from dependence of Hardy-Weinberg equilibrium test P-values on allelic frequency, and (6) demonstrate sensitivity of principal components analysis to SNP selection. The methods are illustrated with examples from the "Gene Environment Association Studies" (GENEVA) program. The results suggest several recommendations for QC/QA in the design and execution of GWAS.

Genetics of Atrial Fibrillation

Article

Apr 2010
Heart Fail Clin

Recent studies of atrial fibrillation (AF) have identified mutations in a series of ion channels; however, these mutations appear to be relatively rare causes of AF. A genome-wide association study has identified novel variants on chromosome 4 associated with AF, although the mechanism of action for these variants remains unknown. Ultimately, a greater understanding of the genetics of AF should yield insights into novel pathways, therapeutic targets, and diagnostic testing for this common arrhythmia.

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts

Article

Feb 2009

Background: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci. Conclusions: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.

Sequence Variants on Chromosome 9p21.3 Confer Risk of Atherosclerotic Stroke

Article

May 2009
ANN NEUROL

Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk. In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1,090 cases, 1,244 control subjects) and the United Kingdom (758 cases, 872 control subjects, 3 SNPs). SNPs significantly associated with ischemic stroke or individual stroke subtypes in either of the screening samples were subsequently genotyped in 2,528 additional cases and 2,189 additional control subjects from Europe and North America. Genotyping of the screening samples demonstrated associations between seven SNPs and atherosclerotic stroke (all p < 0.05). Analysis of the full sample confirmed associations between six SNPs and atherosclerotic stroke in multivariate analyses controlling for demographic variables, coronary artery disease, myocardial infarction, and vascular risk factors (all p < 0.05). The odds ratios for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled odds ratio of 1.21 (95% confidence interval, 1.07-1.37) under both fixed- and random-effects models (p = 0.002). The point estimate for the population attributable risk is 20.1% for atherosclerotic stroke. The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke appears to be independent of its relation to coronary artery disease and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease.

Experience from a multicentre stroke register: A preliminary report

Article

Feb 1976
B WORLD HEALTH ORGAN

S Hatano

In collaboration with 15 centres in 10 countries of Africa, Asia, and Europe, WHO started a pilot study of a community-based stroke register, with standardized methods. Preliminary data were obtained on 6395 new cases of stroke in defined study communities, from May 1971 to September 1974. Information on incidence rates, clinical profiles, diagnosis, management, and course and prognosis for these patients is given.

Adams HP, Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE, TOAST InvestigatorsClassification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke 24:35-41

Article

Feb 1993

The etiology of ischemic stroke affects prognosis, outcome, and management. Trials of therapies for patients with acute stroke should include measurements of responses as influenced by subtype of ischemic stroke. A system for categorization of subtypes of ischemic stroke mainly based on etiology has been developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST). A classification of subtypes was prepared using clinical features and the results of ancillary diagnostic studies. "Possible" and "probable" diagnoses can be made based on the physician's certainty of diagnosis. The usefulness and interrater agreement of the classification were tested by two neurologists who had not participated in the writing of the criteria. The neurologists independently used the TOAST classification system in their bedside evaluation of 20 patients, first based only on clinical features and then after reviewing the results of diagnostic tests. The TOAST classification denotes five subtypes of ischemic stroke: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined etiology, and 5) stroke of undetermined etiology. Using this rating system, interphysician agreement was very high. The two physicians disagreed in only one patient. They were both able to reach a specific etiologic diagnosis in 11 patients, whereas the cause of stroke was not determined in nine. The TOAST stroke subtype classification system is easy to use and has good interobserver agreement. This system should allow investigators to report responses to treatment among important subgroups of patients with ischemic stroke. Clinical trials testing treatments for acute ischemic stroke should include similar methods to diagnose subtypes of stroke.

Interrater Reliability of an Etiologic Classification of Ischemic Stroke

Article

Feb 1995

Precise identification of the cause of stroke is critical to research and clinical practice. Published series of ischemic stroke show considerable variation in the proportion of cases classified as atherosclerotic large-vessel disease, lacunar infarct, cardioembolic stroke, stroke of other known cause, and stroke of undetermined etiology. We describe the development and use of an etiology-specific classification of ischemic stroke. The interrater reliability of the classification is then evaluated. A total of 160 cases of ischemic strokes in young adults were reviewed by paired neurologists who assigned cases to prioritized categories. The results of paired ratings were evaluated for each of the potential causes. Interrater agreement was assessed by means of kappa, which is the chance-adjusted percent agreement. For standard pairs, kappa was fair to good for all causes except lacunar stroke (kappa = 0.31); however, pair-to-pair variation was greatest for lacunar strokes. Strokes of undetermined cause and hematologic/other cause were of borderline fair reliability. The utility of a stroke classification system is dependent on its intended use. An etiologic classification is useful in studies of the epidemiology and pathophysiological basis of stroke. Fair to good reliability for an etiologic classification of stroke can be obtained when criteria are explicit.

Cerebral infarction in young adults: The Baltimore-Washington Cooperative Young Stroke Study

Article

May 1998

Few reports on stroke in young adults have included cases from all community and referral hospitals in a defined geographic region. At 46 hospitals in Baltimore City, 5 central Maryland counties, and Washington, DC, the chart of every patient 15 to 44 years of age with a primary or secondary diagnosis of possible cerebral arterial infarction during 1988 and 1991 was abstracted. Probable and possible etiologies were assigned following written guidelines. Of 428 first strokes, 212 (49.5%) were assigned at least one probable cause, 80 (18.7%) had no probable cause but at least one possible cause, and 136 (31.8%) had no identified probable or possible cause. Of the 212 with at least one probable cause, the distribution of etiologies was cardiac embolism (31.1%), hematologic and other (19.8%), small vessel (lacunar) disease (19.8%), nonatherosclerotic vasculopathy (11.3%), illicit drug use (9.4%), oral contraceptive use (5.2%), large artery atherosclerotic disease (3.8%), and migraine (1.4%). There were an additional 69 recurrent stroke patients. In this hospital-based registry within a region characterized by racial/ethnic diversity, cardiac embolism, hematologic and other causes, and lacunar stroke were the most common etiologies of cerebral infarction in young adults. Nearly a third of both first and recurrent strokes had no identified cause.

Addressing the Heterogeneity of the Ischemic Stroke Phenotype in Human Genetics Research

Article

Jan 2003
STROKE

James F Meschia

Many investigators have approached ischemic stroke as a complex phenotype by dividing the ischemic stroke population into distinct subtypes. The purpose of this study was to review systematically the methods used to subtype ischemic stroke in recent genetic studies. The MEDLINE database was searched for articles pertaining to research on the genetics of human ischemic stroke published from January 2000 through January 2002. Abstracts and full-length reports were then sequentially screened to select articles pertaining to original case-control or cohort studies. The initial search yielded 153 publications. Of 41 relevant articles, ischemic stroke was subtyped in 25 (61%). The most common standard subtyping system was the Cerebrovascular Classification of Diseases III system (9 articles). Of the subtyping systems used, 3 had previously published interrater reliability. The subtyping system was reported to have been prespecified in 1 study. Four articles reported using central adjudication. Two articles reported that the person doing the subtyping was blinded to genotype, and 2 reported that the person doing the genotyping was blinded to the patient's subtype status. When investigators subtyped ischemic stroke, they typically used either nonstandard classification systems or systems of undetermined reliability. Important methodological issues, including blinding and prespecification of the classification system, were rarely reported. Advances in methodology and scientific reporting standards would foster identification of subtype-specific genetic risk factors.

Family History in Ischemic Stroke Before 70 Years of Age: The Sahlgrenska Academy Study on Ischemic Stroke

Article

Aug 2005
STROKE

Results from twin and family history studies of ischemic stroke suggest that future molecular genetic studies should focus on strictly defined stroke subtypes and younger cases. Accordingly, we investigated stroke subtypes, vascular risk factors, and family history in a large study of patients with ischemic stroke onset before age 70 years. Six hundred consecutive white participants with ischemic stroke (18 to 69 years) and 600 age- and sex-matched controls were examined for vascular risk factors and family history of stroke and myocardial infarction (MI). Stroke subtype was defined using Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Family history of stroke was associated with overall ischemic stroke (multivariate odds ratio [OR], 1.75; 95% confidence interval [CI], 1.26 to 2.43), large-vessel disease (LVD) (OR, 1.88; 95% CI, 1.02 to 3.44), small-vessel disease (SVD, OR, 1.79; 95% CI, 1.13 to 2.84), and cryptogenic stroke (OR, 1.70; 95% CI, 1.13 to 2.56), but not with cardioembolic stroke. Family history of MI was strongly associated with LVD (OR, 3.25; 95% CI, 1.74 to 6.07), whereas no significant association were observed for other subtypes. We also found an independent association between family history of stroke and a favorable outcome after 3 months. Family history of stroke is an independent risk factor for ischemic stroke with onset before age 70 years. For the first time to our knowledge, we report this association not only for LVD and SVD but also for cryptogenic stroke, implying that future studies of the genetics of ischemic stroke should target these 3 subtypes.

An evidence-based causative classification system for acute ischemic stroke

Article

Nov 2005

Regular, evidence-based assignment of patients to etiologic stroke categories is essential to enable valid comparison among studies. We designed an algorithm (SSS-TOAST) that incorporated recent advances in stroke imaging and epidemiology to identify the most probable TOAST category in the presence of evidence for multiple mechanisms. Based on the weight of evidence, each TOAST subtype was subdivided into 3 subcategories as "evident", "probable", or "possible". Classification into the subcategories was determined via predefined specific clinical and imaging criteria. These criteria included published risks of ischemic stroke from various mechanisms and published reports of the strength of associations between clinical and imaging features and particular stroke mechanisms. Two neurologists independently assessed 50 consecutively admitted patients with acute ischemic stroke through reviews of abstracted data from medical records. The number of patients classified as "undetermined-unclassified" per the original TOAST system decreased from 38-40% to 4% using the SSS-TOAST system. The kappa value for inter-examiner reliability was 0.78 and 0.90 for the original TOAST and SSS-TOAST respectively. The SSS-TOAST system successfully classifies patients with acute ischemic stroke into determined etiologic categories without sacrificing reliability. The SSS-TOAST is a dynamic algorithm that can accommodate modifications as new epidemiological data accumulate and diagnostic techniques advance.

Variants conferring risk of atrial fibrillation on chromosome 4q25

Article

Aug 2007
NATURE

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.

A Computerized Algorithm for Etiologic Classification of Ischemic Stroke The Causative Classification of Stroke System

Article

Dec 2007
STROKE

The SSS-TOAST is an evidence-based classification algorithm for acute ischemic stroke designed to determine the most likely etiology in the presence of multiple competing mechanisms. In this article, we present an automated version of the SSS-TOAST, the Causative Classification System (CCS), to facilitate its utility in multicenter settings. The CCS is a web-based system that consists of questionnaire-style classification scheme for ischemic stroke (http://ccs.martinos.org). Data entry is provided via checkboxes indicating results of clinical and diagnostic evaluations. The automated algorithm reports the stroke subtype and a description of the classification rationale. We evaluated the reliability of the system via assessment of 50 consecutive patients with ischemic stroke by 5 neurologists from 4 academic stroke centers. The kappa value for inter-examiner agreement was 0.86 (95% CI, 0.81 to 0.91) for the 5-item CCS (large artery atherosclerosis, cardio-aortic embolism, small artery occlusion, other causes, and undetermined causes), 0.85 (95% CI, 0.80 to 0.89) with the undetermined group broken into cryptogenic embolism, other cryptogenic, incomplete evaluation, and unclassified groups (8-item CCS), and 0.80 (95% CI, 0.76 to 0.83) for a 16-item breakdown in which diagnoses were stratified by the level of confidence. The intra-examiner reliability was 0.90 (0.75-1.00) for 5-item, 0.87 (0.73-1.00) for 8-item, and 0.86 (0.75-0.97) for 16-item CCS subtypes. The web-based CCS allows rapid analysis of patient data with excellent intra- and inter-examiner reliability, suggesting a potential utility in improving the fidelity of stroke classification in multicenter trials or research databases in which accurate subtyping is critical.

Australian Stroke Genetics Collaborative; International Stroke Genetics Consortium; Wellcome Trust Case Control Consortium 2. Common variants at 6p21.1 are associated with large artery atheroscle-rotic stroke

Jan 2012
1147-1151

Holliday Eg
Evans Jm Tj Maguire
Koblar
Jannes J Sa
Sturm
Jw

Holliday EG, Maguire JM, Evans TJ, Koblar SA, Jannes J, Sturm JW, et al; Australian Stroke Genetics Collaborative; International Stroke Genetics Consortium; Wellcome Trust Case Control Consortium 2. Common variants at 6p21.1 are associated with large artery atheroscle-rotic stroke. Nat Genet. 2012;44:1147–1151.

Bio-repository of DNA in stroke: a study protocol of three anacestral populations

Jan 2012

Cotlarciuc I Muhammad
Sk
A Maheshwari

Cotlarciuc I, Muhammad SK, Maheshwari A, et al. Bio-repository of DNA in stroke: a study protocol of three anacestral populations. J R Soc Med Cardiovasc Dis. 2012;1(10).

The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project Collection of some of the St George's stroke cohort was supported by project grant support from the Stroke Association

St George

ST. GEORGE'S: The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). Collection of some of the St George's stroke cohort was supported by project grant support from the Stroke Association.

The Ischemic Stroke Genetics Study (ISGS) was supported by the National Institute of Neurological Disorders and Stroke (R01 NS42733; PI James F. Meschia). The Sibling with Ischemic Stroke Study (SWISS) was supported by the National Institute of Neurological Disorders and Stroke (R01 NS39987

Swiss Isgs

ISGS and SWISS: The Ischemic Stroke Genetics Study (ISGS) was supported by the National Institute of Neurological Disorders and Stroke (R01 NS42733; PI James F. Meschia). The Sibling with Ischemic Stroke Study (SWISS) was supported by the National Institute of Neurological Disorders and Stroke (R01 NS39987; PI James F.

Genetics of atrial fibrillation

Jan 2010
Heart Fail Clin
239-247

S A Lubitz
B A Yi
P T Ellinor

Lubitz SA, Yi BA, Ellinor PT. Genetics of atrial fibrillation. Heart Fail Clin. 2010; 6:239-247. [PubMed: 20347792]

Stroke Genetics Network (SiGN) Study Design and Rationale for a Genome-Wide Association Study of Ischemic Stroke Subtypes

Abstract

No full-text available

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