Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.
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ABSTRACT:
SUBMITTER: Xu H
PROVIDER: S-EPMC9858999 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
Publications
Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.
Xu Huichun H Nguyen Kevin K Gaynor Brady J BJ Ling Hua H Zhao Wei W McArdle Patrick F PF O'Connor Timothy D TD Stine O Colin OC Ryan Kathleen A KA Lynch Megan M Smith Jennifer A JA Faul Jessica D JD Hu Yao Y Haessler Jeffrey W JW Fornage Myriam M Kooperberg Charles C On Behalf Of The Trans-Omics For Precision Medicine TOPMed Stroke Working Group Perry James A JA Hong Charles C CC Cole John W JW Pugh Elizabeth E Doheny Kimberly K Kardia Sharon L R SLR Weir David R DR Kittner Steven J SJ Mitchell Braxton D BD
Genes 20221224 1
Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly ass ...[more]
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Project description:Background and purposeThe 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.MethodsDiscovery 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.ResultsGene 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).ConclusionsExome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.
| S-EPMC7606344 | biostudies-literature
Project description:IntroductionTo assess whether the asymmetrical cortical vessel sign (ACVS) on susceptibility-weighted imaging (SWI) could predict 90-day poor outcomes in anterior circulation acute ischemic stroke (AIS) patients treated with recombinant tissue plasminogen activator (r-tPA).MethodsClinical data of consecutive patients with anterior circulation AIS treated with r-tPA were retrospectively analyzed. Clinical variables included age, sex, vascular risk factors, NIHSS score, onset to treatment time, and initial hematologic and neuroimaging findings. Follow-up was performed 90 days after onset. Poor outcome was defined as a modified Rankin scale (mRS) ≥3 at 90 days.ResultsA total of 145 patients were included, 35 (24.1%) patients presented with ACVS (≥Grade 1) on SWI. Fifty-three (36.6%) patients had a poor outcome at 90 days. ACVS (≥Grade 1) occurred in 21 (39.6%) patients with poor outcome compared with 14 (15.2%) patients with favorable outcome (p = .001). Univariate analysis indicated that age, NIHSS score on admission, previous stroke, hemorrhagic transformation, severe intracranial large artery stenosis or occlusion (SILASO), and ACVS were associated with 90-day poor outcome (p < .05). Since SILASO and ACVS were highly correlated and ACVS had different grades, we used three logistic regression models. Results from the three models showed that ACVS was associated with 90-day poor outcome.ConclusionsIn r-tPA-treated patients with anterior circulation AIS, ACVS might be a helpful neuroimaging predictor for poor outcome at 90 days.
| S-EPMC7375089 | biostudies-literature
Project description:The genetic architecture of ischemic stroke is complex and is likely to include rare or low frequency variants with high penetrance and large effect sizes. Such variants are likely to provide important insights into disease pathogenesis compared to common variants with small effect sizes. Because a significant portion of human functional variation may derive from the protein-coding portion of genes we undertook a pilot study to identify variation across the human exome (i.e., the coding exons across the entire human genome) in 10 ischemic stroke cases. Our efforts focused on evaluating the feasibility and identifying the difficulties in this type of research as it applies to ischemic stroke. The cases included 8 African-Americans and 2 Caucasians selected on the basis of similar stroke subtypes and by implementing a case selection algorithm that emphasized the genetic contribution of stroke risk. Following construction of paired-end sequencing libraries, all predicted human exons in each sample were captured and sequenced. Sequencing generated an average of 25.5 million read pairs (75 bp×2) and 3.8 Gbp per sample. After passing quality filters, screening the exomes against dbSNP demonstrated an average of 2839 novel SNPs among African-Americans and 1105 among Caucasians. In an aggregate analysis, 48 genes were identified to have at least one rare variant across all stroke cases. One gene, CSN3, identified by screening our prior GWAS results in conjunction with our exome results, was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated. In conclusion, while rare coding variants may predispose to the risk of ischemic stroke, this fact has yet to be definitively proven. Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined.
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Project description:PURPOSE:Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data. METHODS:We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status. RESULTS:No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10-6; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10-5). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10-6) and among never smokers (N = 790, p = 2.67 × 10-6). CONCLUSIONS:This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.
| S-EPMC5851868 | biostudies-literature
Project description:ObjectiveThe objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems.MethodsStudy subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems.ResultsThe overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58).ConclusionAgreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.
| S-EPMC4223086 | biostudies-literature
Project description:This study aimed to examine the effectiveness of defibrinogen therapy on functional recovery and safety among 1332 consecutive ischemic stroke patients who had not received intravenous thrombolysis with recombinant tissue plasminogen activator. Stroke patients undergoing conservative and relatively individualized multiple-day dosing regimens of defibrinogen therapy between January 1, 2008 and May 30, 2016 were enrolled. Data were analyzed according to functional success (Barthel Index of 95 or 100, mRS of 0 or 1) and safety variables (intracranial hemorrhage, mortality and stroke recurrence). At 12 months, 18.62% (203/1087) of patients were lost to follow-up. The functional success rates were 39.84% (526/1320) and 42.23% (459/1087) as assessed by BI at 3 months and 12 months, respectively. Fifteen patients had asymptomatic intracranial hemorrhage within 24 hours after the initial defibrase administration. During the 14 days after hospitalization, 12 patients were diagnosed with symptomatic intracranial hemorrhage (sICH) and a total of 12 patients died from all causes. At 3 months, 56 patients were dead and 21 patients had recurrent stroke. The percentage of death and recurrence of stroke at 12 months were 6.81% and 3.22%, respectively. Results from the historical control showed no significant differences of functional success were detected between the patients treated with rt-PA within 6 hours of stroke onset in NINDS II and the patients treated with defibrase within 6 hours after stroke in the present study. The multiple-day dosing regimen of defibrinogen therapy using defibrase applied in the present study could achieve functional improvement among acute ischemic stroke patients, with low risks of mortality when compared with other similar studies. However, the efficacy and safety of such a defibrinogenating therapy is needed to be verified by RCTs with large sample size.
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Project description:Backgrounds and Purpose- Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods- We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands' clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results- Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in NOTCH3 and a possibly pathogenic variant in ACAD9 gene were identified. A novel JAK2:c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. COL4A2:c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, GPR142:c.148C>G (p.Leu50Val), and PTPRN2:c.2416A>G (p.Ile806Val); LRRC1 c.808A>G (p.Ile270Val), SLC7A10c.1294dupG (p.Val432fs), IKBKB: c.1070C>T (p.Ala357Val), and OXGR1 c.392G>A (p.Arg131His), respectively. Conclusions- Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.
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Project description:ObjectivesThe aim of our study was to evaluate, in acute ischemic stroke patients, the diagnostic accuracy of the MRI susceptibility vessel sign (SVS) against catheter angiography (DSA) for the detection of the clot and its value in predicting clot location and length.Materials and methodsWe identified consecutive patients (2006-2012) admitted to our center, where 1.5 T MRI is systematically implemented as first-line diagnostic work-up, with: (1) pre-treatment 6-mm-thick multislice 2D T2* sequence; (2) delay from MRI-to-DSA <3 hrs; (3) no fibrinolysis between MRI and DSA. The location and length of SVS on T2* was independently assessed by three readers, and compared per patient, per artery and per segment, to DSA findings, obtained by two different readers. Clot length measured on T2* and DSA were compared using intra-class correlation coefficient (ICC), Bland & Altman test and Passing & Bablok regression analysis.ResultsOn DSA, a clot was present in 85 patients, in 126 of 1190 (10.6%) arteries and 175 of 1870 (9.4%) segments. Sensitivity of the SVS, as sensed by the used protocol at 1.5 T, was 81.1% (69 of 85 patients) and was higher in anterior (55 of 63, 87.3%), than in posterior circulation stroke (14 of 22, 63.6%, p=0.02). Sensitivity/specificity was 69.8/99.6% (per artery) and 76.6/99.7% (per segment). Positive (PPV) and negative predictive value (NPV) and accuracy were all >94%. Inter- and intra-observer ICC was excellent for clot length as measured on T2* (ĸ ≥ 0.97) and as measured on DSA (ĸ ≥ 0.94). Correlation between T2* and DSA for clot length was excellent (ICC: 0.88, 95%CI: 0.81-0.92; Bland & Altman: mean bias of 1.6% [95%CI: -4.7 to 7.8%], Passing & Bablok: 0.91).ConclusionsSVS is a specific marker of clot location in the anterior and posterior circulation. Clot length greater than 6 mm can be reliably measured on T2*.
| S-EPMC3795632 | biostudies-literature
Project description:Background and purposeThe frequency and clinical significance of the susceptibility vessel sign in patients with acute ischemic stroke remains unclear. We aimed to assess its prevalence in patients with acute ischemic stroke undergoing mechanical thrombectomy and to analyze its association with interventional and clinical outcome parameters in that group.Materials and methodsSix hundred seventy-six patients with acute ischemic stroke and admission MR imaging were reviewed retrospectively. Of those, 577 met the eligibility criteria for further analysis. Imaging was performed using a 1.5T or 3T MR imaging scanner. Associations between baseline variables, interventional and clinical outcome parameters, and susceptibility vessel sign were determined with multivariable logistic regression models. Results are shown as adjusted ORs with 95% CIs.ResultsThe susceptibility vessel sign was present in 87.5% (n = 505) of patients and associated with tandem occlusion (adjusted OR, 3.3; 95% CI, 1.1-10.0; P = .032) as well as successful reperfusion, defined as an expanded TICI score of ≥2b (adjusted OR, 2.4; 95% CI, 1.28-4.6; P = .007). The susceptibility vessel sign was independently associated with functional independence (mRS ≤ 2: adjusted OR, 2.1; 95% CI, 1.1-4.0; P = .028) and lower mortality (adjusted OR, 0.4; 95% CI, 0.2-0.7; P = .003) at 90 days, even after adjusting for successful reperfusion. The susceptibility vessel sign did not influence the number of passes performed during mechanical thrombectomy, the first-pass reperfusion, or the risk of peri- or postinterventional complications.ConclusionsThe susceptibility vessel sign is an MR imaging phenomenon frequently observed in patients with acute ischemic stroke and is associated with successful reperfusion after mechanical thrombectomy. However, superior clinical functional outcome and lower mortality noted in patients showing the susceptibility vessel sign could not be entirely attributed to higher reperfusion rates.
| S-EPMC8583274 | biostudies-literature
Project description:Host genetic variability may contribute to susceptibility of bacterial meningitis, but which genes contribute to the susceptibility to this complex disease remains undefined. We performed a genetic association study in 469 community-acquired pneumococcal meningitis cases and 2072 population-based controls from the Utrecht Health Project in order to find genetic variants associated with pneumococcal meningitis susceptibility. A HumanExome BeadChip was used to genotype 102,097 SNPs in the collected DNA samples. Associations were tested with the Fisher exact test. None of the genetic variants tested reached Bonferroni corrected significance (p-value <5 × 10(-7)). Our strongest signals associated with susceptibility to pneumococcal meningitis were rs139064549 on chromosome 1 in the COL11A1 gene (p = 1.51 × 10(-6); G allele OR 3.21 [95% CI 2.05-5.02]) and rs9309464 in the EXOC6B gene on chromosome 2 (p = 6.01 × 10(-5); G allele OR 0.66 [95% CI 0.54-0.81]). The sequence kernel association test (SKAT) tests for associations between multiple variants in a gene region and pneumococcal meningitis susceptibility yielded one significant associated gene namely COL11A1 (p = 1.03 × 10(-7)). Replication studies are needed to validate these results. If replicated, the functionality of these genetic variations should be further studied to identify by which means they influence the pathophysiology of pneumococcal meningitis.
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