Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study.

Clinical epidemiolog

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

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

Genetic associations with brain microbleeds: Systematic review and meta-analyses

We performed a systematic review and meta-analyses to assess the evidence for genetic associations with brain microbleeds (BMBs).status: publishe

Physiological Monitoring in Acute Stroke: A Literature Review

Aim. This paper is a report of a review of the literature that considers how physiological parameters may affect outcome after stroke and the implications of this evidence for monitoring. Background. Throughout the world, the incidence of first-ever stroke is approximately 200 per 100,000 people per year [Sudlow et al. (1997) Stroke 28, 491]. Stroke is the third most common cause of mortality [Sarti et al. (2000) Stroke 31, 1588] and causes 5.54 million deaths worldwide [Murray & Lopez (1997) Lancet 349, 268]. Physiological monitoring is considered a fundamental component of acute stroke care. Currently, the strength of evidence to support its use and identify its components is unclear. Nurse-led physiological assessment and subsequent interventions in acute stroke may have the potential to improve survival and reduce disability. Data sources. Online bibliographic databases from 1966 to 2007, including MEDLINE, EMBASE, CINAHL, AMED, Cochrane and ZETOC, were searched systematically. We identified 475 published papers relating to blood pressure, oxygen saturation and positioning, blood glucose and body temperature. Review methods. Titles and abstracts were reviewed independently by two reviewers and 61 relevant studies were read in full. The quality of included studies was assessed and proformas were used to record detailed data. A narrative synthesis described how the evidence from the papers could inform our understanding of physiological parameters and their association with outcome. Results. Current evidence suggests that patient outcome is worse when physiological parameters deviate from 'normal' in the acute phase of stroke. Conclusions. The evidence supports the need for monitoring and recording of blood pressure, oxygen saturation (including consideration of positioning), blood glucose and body temperature in the acute phase of stroke. This review has reinforced the importance of monitoring physiological parameters in the acute phase of stroke and adds support to the recommendation that monitoring should play a key role within nursing care

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (vol 50, pg 524, 2018)

The Author(s), under exclusive licence to Springer Nature America, Inc. An amendment to this paper has been published and can be accessed via a link at the top of the paper

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.Paroxysmal Cerebral Disorder