Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia.

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112?151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.Molecular Psychiatry advance online publication, 26 January 2016; doi:10.1038/mp.2015.225

Developing a multivariable prediction model for functional outcome after reperfusion therapy for acute ischaemic stroke: study protocol for the Targeting Optimal Thrombolysis Outcomes (TOTO) multicentre cohort study

INTRODUCTION: Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is the only approved pharmacological reperfusion therapy for acute ischaemic stroke. Despite population benefit, IVT is not equally effective in all patients, nor is it without significant risk. Uncertain treatment outcome prediction complicates patient treatment selection. This study will develop and validate predictive algorithms for IVT response, using clinical, radiological and blood-based biomarker measures. A secondary objective is to develop predictive algorithms for endovascular thrombectomy (EVT), which has been proven as an effective reperfusion therapy since study inception. METHODS AND ANALYSIS: The Targeting Optimal Thrombolysis Outcomes Study is a multicenter prospective cohort study of ischaemic stroke patients treated at participating Australian Stroke Centres with IVT and/or EVT. Patients undergo neuroimaging using multimodal CT or MRI at baseline with repeat neuroimaging 24 hours post-treatment. Baseline and follow-up blood samples are provided for research use. The primary outcome is good functional outcome at 90 days poststroke, defined as a modified Rankin Scale (mRS) Score of 0-2. Secondary outcomes are reperfusion, recanalisation, infarct core growth, change in stroke severity, poor functional outcome, excellent functional outcome and ordinal mRS at 90 days. Primary predictive models will be developed and validated in patients treated only with rt-PA. Models will be built using regression methods and include clinical variables, radiological measures from multimodal neuroimaging and blood-based biomarkers measured by mass spectrometry. Predictive accuracy will be quantified using c-statistics and R2. In secondary analyses, models will be developed in patients treated using EVT, with or without prior IVT, reflecting practice changes since original study design. ETHICS AND DISSEMINATION: Patients, or relatives when patients could not consent, provide written informed consent to participate. This study received approval from the Hunter New England Local Health District Human Research Ethics Committee (reference 14/10/15/4.02). Findings will be disseminated via peer-reviewed publications and conference presentations.Elizabeth Holliday ... Marten Snel ... Simon Koblar ... Monica Hamilton-Bruce ... Timothy Kleinig ... Paul J Trim ... et al

No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin

Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events

Genetic overlap between diagnostic subtypes of ischemic stroke

Background and Purpose: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Methods: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. Results: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10-4) and profile scores (rg=0.72; 95% confid

Early- Onset Stroke and Vasculopathy Associated with Mutations in ADA2

Adenosine deaminase 2 (ADA2) is an enzyme involved in purine metabolism and a growth factor that influences the development of endothelial cells and leukocytes. This study shows that defects in ADA2 cause recurrent fevers, vascular pathologic features, and mild immunodeficiency. Patients with autoinflammatory disease sometimes present with clinical findings that encompass multiple organ systems.(1) Three unrelated children presented to the National Institutes of Health (NIH) Clinical Center with intermittent fevers, recurrent lacunar strokes, elevated levels of acute-phase reactants, livedoid rash, hepatosplenomegaly, and hypogammaglobulinemia. Collectively, these findings do not easily fit with any of the known inherited autoinflammatory diseases. Hereditary or acquired vascular disorders can have protean manifestations yet be caused by mutations in a single gene. Diseases such as the Aicardi-Goutieres syndrome,(2),(3) polypoidal choroidal vasculopathy,(4) sickle cell anemia,(5) livedoid vasculopathy,(6) and the small-vessel vasculitides(7),(8) are examples of systemic ...</p

Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p 5 7.12 3 10-11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p 5 0.695).Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 case

Serum magnesium and calcium levels in relation to ischemic stroke : Mendelian randomization study

ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 7 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 7 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelian randomization study.

ObjectiveTo examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.MethodsWe undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.ResultsA 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 x 10(-8)). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 x 10(-3)) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 x 10(-3)) when compared with that for CHD.ConclusionsIn contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed

DNA methylation analyses identify an intronic ZDHHC6 locus associated with time to recurrent stroke in the Vitamin Intervention for Stroke Prevention (VISP) clinical trial

Altres ajuts: National Institutes of Health (grant U01HG005160); National Human Genome Research Institute (Supplement U01HG005160-03S1); American Heart Association Scientist Development Award (12SDG9180012); Faith Christian Center International (Charlottesville, VA). National Institute of Neurological Disorders and Stroke (R01 NS34447).Aberrant DNA methylation profiles have been implicated in numerous cardiovascular diseases; however, few studies have investigated how these epigenetic modifications contribute to stroke recurrence. The aim of this study was to identify methylation loci associated with the time to recurrent cerebro- and cardiovascular events in individuals of European and African descent. DNA methylation profiles were generated for 180 individuals from the Vitamin Intervention for Stroke Prevention clinical trial using Illumina HumanMethylation 450K BeadChip microarrays, resulting in beta values for 470,871 autosomal CpG sites. Ethnicity-stratified survival analyses were performed using Cox Proportional Hazards regression models for associations between each methylation locus and the time to recurrent stroke or composite vascular event. Results were validated in the Vall d'Hebron University Hospital cohort from Barcelona, Spain. Network analyses of the methylation loci were generated using weighted gene coexpression network analysis. Primary analysis identified four significant loci, cg04059318, ch.2.81927627R, cg03584380, and cg24875416, associated with time to recurrent stroke. Secondary analysis identified three loci, cg00076998, cg16758041, and cg02365967, associated with time to composite vascular endpoint. Locus cg03584380, which is located in an intron of ZDHHC6, was replicated in the Vall d'Hebron University Hospital cohort. The results from this study implicate the degree of methylation at cg03584380 is associated with the time of recurrence for stroke or composite vascular events across two ethnically diverse groups. Furthermore, modules of loci were associated with clinical traits and blood biomarkers including previous number of strokes, prothrombin fragments 1 + 2, thrombomodulin, thrombin-antithrombin complex, triglyceride levels, and tissue plasminogen activator. Ultimately, these loci could serve as potential epigenetic biomarkers that could identify at-risk individuals in recurrence-prone populations