| 1. |
- Pulit, SL, et al.
(författare)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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Ingår i: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Tidskriftsartikel (refereegranskat)abstract
- 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.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.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.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.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 2. |
- Rannikmae, K, et al.
(författare)
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Physician-Confirmed and Administrative Definitions of Stroke in UK Biobank Reflect the Same Underlying Genetic Trait
- 2022
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 12, s. 787107-
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Tidskriftsartikel (refereegranskat)abstract
- Stroke in UK Biobank (UKB) is ascertained via linkages to coded administrative datasets and self-report. We studied the accuracy of these codes using genetic validation.MethodsWe compiled stroke-specific and broad cerebrovascular disease (CVD) code lists (Read V2/V3, ICD-9/-10) for medical settings (hospital, death record, primary care) and self-report. Among 408,210 UKB participants, we identified all with a relevant code, creating 12 stroke definitions based on the code type and source. We performed genome-wide association studies (GWASs) for each definition, comparing summary results against the largest published stroke GWAS (MEGASTROKE), assessing genetic correlations, and replicating 32 stroke-associated loci.ResultsThe stroke case numbers identified varied widely from 3,976 (primary care stroke-specific codes) to 19,449 (all codes, all sources). All 12 UKB stroke definitions were significantly correlated with the MEGASTROKE summary GWAS results (rg.81-1) and each other (rg.4-1). However, Bonferroni-corrected confidence intervals were wide, suggesting limited precision of some results. Six previously reported stroke-associated loci were replicated using ≥1 UKB stroke definition.ConclusionsStroke case numbers in UKB depend on the code source and type used, with a 5-fold difference in the maximum case-sample size. All stroke definitions are significantly genetically correlated with the largest stroke GWAS to date.
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| 3. |
- Rannikmäe, K., et al.
(författare)
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Reliability of intracerebral hemorrhage classification systems: A systematic review
- 2016
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 11:6, s. 626-636
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accurately distinguishing non-traumatic intracerebral hemorrhage (ICH) subtypes is important since they may have different risk factors, causal pathways, management, and prognosis. We systematically assessed the inter- and intra-rater reliability of ICH classification systems. Methods: We sought all available reliability assessments of anatomical and mechanistic ICH classification systems from electronic databases and personal contacts until October 2014. We assessed included studies’ characteristics, reporting quality and potential for bias; summarized reliability with kappa value forest plots; and performed meta-analyses of the proportion of cases classified into each subtype. Summary of review: We included 8 of 2152 studies identified. Inter- and intra-rater reliabilities were substantial to perfect for anatomical and mechanistic systems (inter-rater kappa values: anatomical 0.78–0.97 [six studies, 518 cases], mechanistic 0.89–0.93 [three studies, 510 cases]; intra-rater kappas: anatomical 0.80–1 [three studies, 137 cases], mechanistic 0.92–0.93 [two studies, 368 cases]). Reporting quality varied but no study fulfilled all criteria and none was free from potential bias. All reliability studies were performed with experienced raters in specialist centers. Proportions of ICH subtypes were largely consistent with previous reports suggesting that included studies are appropriately representative. Conclusions: Reliability of existing classification systems appears excellent but is unknown outside specialist centers with experienced raters. Future reliability comparisons should be facilitated by studies following recently published reporting guidelines. © 2016, © 2016 World Stroke Organization.
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| 4. |
- Menietti, J. D., et al.
(författare)
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Survey of Saturn Z-mode emission
- 2015
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 120:8, s. 6176-6187
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Tidskriftsartikel (refereegranskat)abstract
- Because of the role of Z-mode emission in the diffusive scattering and resonant acceleration of electrons, we conduct a survey of intensity in the Saturn inner magnetosphere. Z mode is primarily observed as 5kHz narrowband emission in the lower density regions where the ratio of cyclotron to plasma frequency, f(c)/f(p)>1 to which we limit this study. This occurs at Saturn along the inner edge of the Enceladus torus near the equator and at higher latitudes. We present profiles and parametric fits of intensity as a function of frequency, radius, latitude, and local time. The magnetic field intensity levels are lower than chorus, but the electric field intensities are comparable. We conclude that Z-mode wave-particle interactions may make a significant contribution to electron acceleration in the inner magnetosphere of Saturn, supplementing acceleration produced by chorus emission.
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| 5. |
- Wild, J. A., et al.
(författare)
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Midnight sector observations of auroral omega bands
- 2011
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 116, s. A00I30-
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Tidskriftsartikel (refereegranskat)abstract
- We present observations of auroral omega bands on 28 September 2009. Although generally associated with the substorm recovery phase and typically observed in the morning sector, the features presented here occurred just after expansion phase onset and were observed in the midnight sector, dawnward of the onset region. An all-sky imager located in northeastern Iceland revealed that the omega bands were similar to 150 x 200 km in size and propagated eastward at similar to 0.4 km s(-1) while a colocated ground magnetometer recorded the simultaneous occurrence of Ps6 pulsations. Although somewhat smaller and slower moving than the majority of previously reported omega bands, the observed structures are clear examples of this phenomenon, albeit in an atypical location and unusually early in the substorm cycle. The THEMIS C probe provided detailed measurements of the upstream interplanetary environment, while the Cluster satellites were located in the tail plasma sheet conjugate to the ground-based all-sky imager. The Cluster satellites observed bursts of 0.1-3 keV electrons moving parallel to the magnetic field toward the Northern Hemisphere auroral ionosphere; these bursts were associated with increased levels of field-aligned Poynting flux. The in situ measurements are consistent with electron acceleration via shear Alfven waves in the plasma sheet similar to 8 R-E tailward of the Earth. Although a one-to-one association between auroral and magnetospheric features was not found, our observations suggest that Alfven waves in the plasma sheet are responsible for field-aligned currents that cause Ps6 pulsations and auroral brightening in the ionosphere. Our findings agree with the conclusions of earlier studies that auroral omega bands have a source mechanism in the midtail plasma sheet.
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