scholarly journals Exome Array Analysis of Early-Onset Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3356-3360
Author(s):  
Thomas Jaworek ◽  
Kathleen A. Ryan ◽  
Brady J. Gaynor ◽  
Patrick F. McArdle ◽  
Oscar C. Stine ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Early Onset ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Population Level ◽  
Small Vessel ◽  
Stroke Treatment ◽  
Functional Variants ◽  
Individual Snps

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

scholarly journals Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Yalan Li ◽  
Jun Lu ◽  
Jie Wang ◽  
Peizhi Deng ◽  
Changjiang Meng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Cytokines ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Outcome Data ◽  
Sensitivity Analyses ◽  
A Genome

Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear.Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results.Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89–0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88–0.99, unadjusted p &lt; 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke.Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.

Abstract 152: Genome-wide Association Study of Early-Onset Ischemic Stroke Identifies Novel Locus on Chromosome 12 Near BCL7A/MLXIP

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Thomas Jaworek ◽  
Steven J Kittner ◽  
Christina Jern ◽  
Frank Erik de Leeuw ◽  
Martin Dichgans ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ischemic Stroke ◽  
Effect Size ◽  
Early Onset ◽  
Drug Targets ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
European Ancestry ◽  
Subtype Specificity ◽  
Genome Wide

Introduction: Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets relevant to later-onset disease. Few studies have investigated the role of common genetic variation in the etiology of early-onset ischemic stroke (IS). Methods: We performed a GWAS meta-analysis of 38 studies from 10 countries, comprised of 5,847 IS cases of European ancestry under age 60 and 32,533 controls. Results: We identified two genome-wide significant (p< 5 x 10 -8 ) loci (see Figure). The ABO locus has previously been associated with venous thrombosis and ischemic stroke in predominantly older adults, but the effect size of our top SNP (OR 1.18; p = 9.1 x 10 -12 ) is larger than the effect size for this same SNP in MEGASTROKE (OR: 1.05; p = 6.5 x 10 -5 ). The lead SNP at the BCL7A/MLXIP locus is a novel GWAS finding for stroke (OR 1.14, 95% CI 1.08-1.19; p = 1.7 x 10 -8 ) and is noteworthy because of prior reports linking SNPs in these genes to BMI and blood pressure. Conclusions: We identified a novel locus that is near variants associated with BMI and blood pressure. Further studies are needed to confirm this locus, examine subtype specificity, and determine its function. The larger effect size observed at the ABO in this early-onset IS sample compared to older-onset IS samples is consistent with a larger role for prothrombotic mechanisms in early-onset IS.

scholarly journals Using a Two-Sample Mendelian Randomization Method in Assessing the Causal Relationships Between Human Blood Metabolites and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Zixian Wang ◽  
Shiyu Chen ◽  
Qian Zhu ◽  
Yonglin Wu ◽  
Guifeng Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Blood ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Blood Metabolites ◽  
Causal Relationships

Background: Heart failure (HF) is the main cause of morbidity and mortality worldwide, and metabolic dysfunction is an important factor related to HF pathogenesis and development. However, the causal effect of blood metabolites on HF remains unclear.Objectives: Our chief aim is to investigate the causal relationships between human blood metabolites and HF risk.Methods: We used an unbiased two-sample Mendelian randomization (MR) approach to assess the causal relationships between 486 human blood metabolites and HF risk. Exposure information was obtained from Sample 1, which is the largest metabolome-based genome-wide association study (mGWAS) data containing 7,824 Europeans. Outcome information was obtained from Sample 2, which is based on the results of a large-scale GWAS meta-analysis of HF and contains 47,309 cases and 930,014 controls of Europeans. The inverse variance weighted (IVW) model was used as the primary two-sample MR analysis method and followed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis.Results: We observed that 11 known metabolites were potentially related to the risk of HF after using the IVW method (P &lt; 0.05). After adding another four MR models and performing sensitivity analyses, we found a 1-SD increase in the xenobiotics 4-vinylphenol sulfate was associated with ~22% higher risk of HF (OR [95%CI], 1.22 [1.07–1.38]).Conclusions: We revealed that the 4-vinylphenol sulfate may nominally increase the risk of HF by 22% after using a two-sample MR approach. Our findings may provide novel insights into the pathogenesis underlying HF and novel strategies for HF prevention.

scholarly journals Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection

2016 ◽  
Author(s):  
Antonio F Pardiñas ◽  
Peter Holmans ◽  
Andrew J Pocklington ◽  
Valentina Escott-Price ◽  
Stephan Ripke ◽  
...  
Keyword(s):  
Large Scale ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Meta Analysis ◽  
Single Gene ◽  
Poor Quality ◽  
Background Selection ◽  
Loss Of Function ◽  
Risk Variants ◽  
Genomic Studies

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide such insight. We report the largest single cohort genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data we identify 50 novel GWAS loci. Using gene-wide association statistics we implicate an additional set of 22 novel associations that map onto a single gene. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection. Associations point to novel areas of biology (e.g. metabotropic GABA-B signalling and acetyl cholinesterase), reinforce those implicated in earlier GWAS studies (e.g. calcium channel function), converge with earlier rare variants studies (e.g. NRXN1, GABAergic signalling), identify novel overlaps with autism (e.g. RBFOX1, FOXP1, FOXG1), and support early controversial candidate gene hypotheses (e.g. ERBB4 implicating neuregulin signalling). We also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. These findings provide novel insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation intolerant genes and suggest a mechanism by which common risk variants are maintained in the population.

scholarly journals Retinal Microvascular Changes in Subtypes of Ischemic Stroke

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying Zhao ◽  
Bing Yang ◽  
An-Ding Xu ◽  
Yi-Wen Ruan ◽  
Ying Xu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Large Scale ◽  
Causal Explanation ◽  
Characteristic Curve ◽  
Underlying Mechanism ◽  
Stroke Subtype ◽  
Stroke Treatment ◽  
Disk Diameter ◽  
Retinal Microvasculature ◽  
Fundus Photographs

Aims: Retinal microvasculature shares prominent similarities with the brain vasculature. We aimed to assess the association between retinal microvasculature and subtypes of ischemic stroke.Method: We consecutively enrolled ischemic stroke patients within 7 days of onset, who met the criteria of subtype of atherothrombosis (AT), small artery disease (SAD), or cardioembolism (CE) according to a modified version of the Trial of Org 10172 in Acute Stroke Treatment (NEW-TOAST). Digital fundus photographs were taken within 72 h of hospital admission using a digital camera (Topcon TRC-50DX), and fundus photographs were semi-automatically measured by software (Canvus 14 and NeuroLucida) for retinal vasculature parameters.Results: A total of 141 patients were enrolled, including 72 with AT, 54 with SAD, and 15 with CE. AT subtype patients had the widest mean venular diameter within 0.5–1.0 disk diameter (MVD0.5−1.0DD) followed by SAD and CE subtypes (86.37 ± 13.49 vs. 83.55 ± 11.54 vs. 77.90 ± 8.50, respectively, P = 0.047); CE subtype patients had the highest mean arteriovenous ratio within 0.5–1.0 disk diameter (MAVR0.5−1.0DD) followed by the AT and SAD subtype groups (0.97 ± 0.03 vs. 0.89 ± 0.99 vs. 0.89 ± 0.11, respectively, P = 0.010); SAD subtype patients were found with the highest mean venular tortuosity within 0.0–2.0 disk diameter (MVT0.0−2.0DD) followed by the AT and CE subtypes (1.0294 ± 0.0081 vs. 1.0259 ± 0.0084 vs. 1.0243 ± 0.0066, respectively, P = 0.024). After adjusting for clinic characteristics, MVD0.5−1.0DD was significantly different among AT, SAD, and CE subtypes (P = 0.033). By receiver operating characteristic curve analysis, MVD0.5−1.0DD predicted the AT subtype (area 0.690, 95% confidence interval, 0.566–0.815), with a cutoff value of 82.23 μm (sensitivity 61.1%, specificity 73.3%).Conclusion: Retinal MVD0.5−1.0DD (&gt;82.23 μm) might be associated with the AT stroke subtype; however, we need large-scale prospective studies in future to explore the underlying mechanism and causal explanation for this finding.

Abstract TP80: Imaging Characteristics of Methamphetamine-Associated Ischemic Strokes

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Nhayoung Hwang ◽  
Sandeep Walia ◽  
Kwan Ng ◽  
Alan Yee
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Strong Association ◽  
Significant Proportion ◽  
Small Vessel ◽  
Underrepresented Minority ◽  
Term Care ◽  
Stroke Treatment ◽  
Imaging Characteristics ◽  
Toast Criteria

Objective: To examine the clinical and neuroimaging characteristics in patients with acute ischemic stroke and concurrent methamphetamine (meth) use. Introduction: Meth is a highly addictive stimulant with harmful effects that lead to cardiovascular disease and stroke. Despite a strong association between meth use and increased cerebrovascular risk, detailed descriptions of clinical and neuroradiologic characteristics in larger cohorts are lacking. Methods: Single-center retrospective analysis of consecutive adults admitted for acute ischemic stroke and meth-positive toxicology between 2016 and 2019. Stroke imaging characteristics, including suspected etiologic mechanism as defined by Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, were documented. Results: Ninety patients were admitted with radiologically confirmed acute ischemic stroke and meth exposure. The average age was 55 years (range, 36-77 years) and 69% were male. Although 47% were Caucasian, nearly half were from an underrepresented minority ethnic/racial group (24% Black, 8% Hispanic/Latino, 9% Asian/Pacific Islander). A multiplicity of strokes was seen in the majority of cases (57%), and 31% affected the bilateral hemispheres. Although 91% of all cases had subcortical involvement, only 34% were purely subcortical of which one-half had brainstem infarctions. The middle cerebral artery distribution was affected most commonly (71%) while multiple vascular territories were involved in 30% of cases. The most frequently encountered stroke subtypes were small vessel occlusion (27%) and a cardioembolic source (26%) as defined by the TOAST criteria. A substantial proportion of patients (31%) were discharged to a rehabilitation or nursing facility, dispositions with high predictive value for unfavorable post-stroke outcomes. Moreover, 15% of patients died during their hospitalization. Conclusion: Meth-associated acute ischemic stroke is a multicultural problem with variable widespread effects throughout the cerebrum. Although small vessel vasculopathy is suspected in most, a significant proportion is due to proximal embolic sources. Long-term care is often required in survivors, and nearly 1 in 6 died during their hospitalization.

Abstract 2597: Centralized and Study-specific Phenotyping in a Large-scale Stroke Genetics Study: An Analysis from the NINDS Stroke Genetics Network (SiGN)

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Bradford B Worrall ◽  
Alejandro Rabinstein ◽  
Dale M Gamble ◽  
Kevin M Barrett ◽  
Shaneela Malik ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Large Scale ◽  
Association Studies ◽  
Web Based ◽  
Stroke Treatment ◽  
Automated Algorithm ◽  
Genome Association ◽  
Whole Genome Association ◽  
Toast Classification ◽  
User Friendly

Background: The Stroke Genetics Network (SiGN) funded by the NINDS aims to identify genetic risk factors in ischemic stroke using whole-genome association studies (GWAS). High quality phenotyping is crucial to successful application of GWAS. As a heterogenous disorder, stroke poses specific challenges. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification is a broadly used, but its validity is challenged especially when performed by multiple investigators with differing interpretations of the system. The Causative Classification System for Ischemic Stroke (CCS) system is a new, web-based, and computerized algorithm that integrates clinical, diagnostic, and etiologic stroke characteristics in an evidence-based manner ( ccs.mgh.harvard.edu ) to generate subtypes. Methods: In planning the SiGN proposal, a sample of 20 coded charts were collected from a subset of participating studies to assess feasibility of central adjudication and comparability to study-specific TOAST. Two central adjudicators reviewed all records and generated TOAST and CCS subtypes. These were compared to study-specific TOAST subtype and the CCS phenotype generated for SiGN by local trained adjudicators. CCS data is now available for 7134 included cases using both a 5 and a 7 category system as defined in the table . Results: All 4 phenotypes were available for 115 ischemic stroke cases from 6 studies in SiGN. Basic demographics were 54% women, 63% white, and median age between 65-74. Table 1 provides the agreement between the various subtypes. Table 2 describes the types of disagreement. Conclusions: Central adjudication with only two adjudicators and curated medical records yielded more consistent subtyping independent of phenotyping system. The agreement for TOAST was higher than published rates by independent groups (∼0.50). In contrast, the agreement for CCS was lower than previously published (0.85-0.95). Site adjudicators' familiarity with TOAST and inexperience with CCS may contribute. Although CCS is an automated algorithm and has a number of user friendly features, our findings suggest that formal training and certification process before starting to use CCS may be worthwhile to achieve optimal benefit from the system.

scholarly journals A Further Comment on ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ by Lam et al.

2018 ◽  
Vol 21 (6) ◽  
pp. 538-545 ◽  
Author(s):  
W. D. Hill
Keyword(s):  
Cognitive Ability ◽  
Drug Targets ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Tissue Specific ◽  
Nootropic Drug ◽  
Genome Wide ◽  
Quality Control Metrics

Lam et al. (2018) respond to a commentary of their paper entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ Lam et al. (2017). While Lam et al. (2018) have now provided the recommended quality control metrics for their paper, problems remain. Specifically, Lam et al. (2018) do not dispute that the results of their multi-trait analysis of genome-wide association study (MTAG) analysis has produced a phenotype with a genetic correlation of one with three measures of education, but do claim the associations found are specific to the trait of cognitive ability. In this brief paper, it is empirically demonstrated that the phenotype derived by Lam et al. (2017) is more genetically similar to education than cognitive ability. In addition, it is shown that of the genome-wide significant loci identified by Lam et al. (2017) are loci that are associated with education rather than with cognitive ability.

scholarly journals Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lawrence Shih-Hsin Wu ◽  
Ming-Chyi Huang ◽  
Cathy Shen-Jang Fann ◽  
Hsien-Yuan Lane ◽  
Chian-Jue Kuo ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Association Study ◽  
Early Onset ◽  
Genome Wide Association Study ◽  
Genetic Locus ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Chinese Descent

AbstractThe search for susceptibility genes underlying the heterogeneous bipolar disorder has been inconclusive, often with irreproducible results. There is a hope that narrowing the phenotypes will increase the power of genetic analysis. Early-onset bipolar disorder is thought to be a genetically homogeneous subtype with greater symptom severity. We conducted a genome-wide association study (GWAS) for this subtype in bipolar I (BPI) disorder. Study participants included 1779 patients of Han Chinese descent with BPI disorder recruited by the Taiwan Bipolar Consortium. We conducted phenotype assessment using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry and prepared a life chart with graphic depiction of lifetime clinical course for each of the BPI patient recruited. The assessment of onset age was based on this life chart with early onset defined as ≤20 years of age. We performed GWAS in a discovery group of 516 early-onset and 790 non-early-onset BPI patients, followed by a replication study in an independent group of 153 early-onset and 320 non-early-onset BPI patients and a meta-analysis with these two groups. The SNP rs11127876, located in the intron of CADM2, showed association with early-onset BPI in the discovery cohort (P = 7.04 × 10−8) and in the test of replication (P = 0.0354). After meta-analysis, this SNP was demonstrated to be a new genetic locus in CADM2 gene associated with early-onset BPI disorder (P = 5.19 × 10−8).

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