| 1. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Block, Lars P, et al.
(författare)
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Advantages of electric circuit models for treating the substorm breakup problem
- 1998
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Ingår i: JOURNAL OF GEOPHYSICAL RESEARCH-SPACE PHYSICS. ; 103, s. 6913-6916
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Tidskriftsartikel (refereegranskat)abstract
- It is shown, by using a circuit model for the magnetospheric current system, that the substorm breakup can be triggered either by some instability anywhere in the circuit or by a decrease in the generator emf, i.e., a northward turning of the interplanetary magnetic field.
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| 3. |
- Chauhan, G., et al.
(författare)
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Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
- 2019
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:5
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10(-8); and LINC00539/ZDHHC20, p = 5.82 x 10(-9). Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p([BI]) = 9.38 x 10(-25); p([SSBI]) = 5.23 x 10(-14) for hypertension), smoking (p([BI]) = 4.4 x 10(-10); p([SSBI]) = 1.2 x 10(-4)), diabetes (p([BI]) = 1.7 x 10(-8); p([SSBI]) = 2.8 x 10(-3)), previous cardiovascular disease (p([BI]) = 1.0 x 10(-18); p([SSBI]) = 2.3 x 10(-7)), stroke (p([BI]) = 3.9 x 10(-69); p([SSBI]) = 3.2 x 10(-24)), and MRI-defined white matter hyperintensity burden (p([BI]) = 1.43 x 10(-157); p([SSBI]) = 3.16 x 10(-106)), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p 0.0022), without indication of directional pleiotropy.ConclusionIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
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| 4. |
- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 5. |
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| 6. |
- Rothwell, P.L., et al.
(författare)
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A new model for auroral breakup during substorms
- 1989
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Ingår i: IEEE Transactions on Plasma Science. - : Institute of Electrical and Electronics Engineers (IEEE). - 0093-3813 .- 1939-9375. ; 17, s. 150-157
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Tidskriftsartikel (refereegranskat)
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| 7. |
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| 8. |
- Rothwell, P.L., et al.
(författare)
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Acceleration and Stochastic Heating of Ions Drifting Through an Auroral Arc
- 1992
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 97, s. 19333-19339
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Tidskriftsartikel (refereegranskat)abstract
- We find that ions E x B drifting through an auroral arc can undergo transverse acceleration and stochastic heating. This result is very analogous to recent work regarding similar phenomena in the magnetotail (Buchner and Zelenyi, 1990; Chen and Palmadesso, 1986; Brittnacher and Whipple, 199 1). An analytic expression for the maximum arc width for which chaotic behavior is present is derived and numerically verified. We find, for example, that a 1.5-km-thick arc at LAMBDA = 65-degrees requires a minimum potential drop of 3 kV for transverse ion acceleration and heating to occur. Thicker arcs require higher potential drops for stochasticity to occur. This mechanism could be a source for conic ions.
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| 9. |
- Rothwell, P.L., et al.
(författare)
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Inertial currents and substorm onsets
- 1996
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Ingår i: European Space Agency, (Special Publication) ESA SP-389. - 0379-6566. ; , s. 447-452
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Tidskriftsartikel (refereegranskat)abstract
- When magnetic field lines are sufficiently stretched during the substorm growth phase, in the equatorial plane the earthward ExB ion drift velocity can become comparable to the ion gyration velocity. Under these conditions inertial currents can become quite important. Using a two-dimensional model we find that O+ ions injected from the ionosphere into the equatorial plane at high latitudes will drift eastward at radial distances less than -10 RE because the inertial drift dominates and westward at distances closer to the earth because the magnetic gradient drift dominates. The inertial eastward drift gives rise to a current which in terms of JxB is consistent with the convective deceleration of the earthward drift velocity due to higher values of B. Similarly, momentum balance requires that the convective acceleration of the westward drift velocity should be consistent with a tailward inertial current. Therefore, an equatorial current wedge system with eastward and tailward current components naturally arises from the ion dynamics. In a future paper a three-dimensional treatment will determine whether curvature drift masks the eastward inertial drift of the oxygen ions.
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| 10. |
- Rothwell, P.L., et al.
(författare)
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O+ phase bunching and auroral arc structure
- 1994
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 99, s. 2461-2470
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Tidskriftsartikel (refereegranskat)abstract
- The equations of motion are solved for ions moving in a model electric field that corresponds to the nightside equatorial region df the magnetosphere. The model represents the poleward region of the Harang discontinuity mapped to the magnetosphere. Within this region the model electric field has a constant earthward gradient superimposed on a constant dawn-to-dusk electric field. In combination with the earthward drift motion due to the dawn-to-dusk field, the electric field gradient introduces an earthward inertia drift, which is proportional to the ion mass and therefore faster for O+ ions than for H+ ions or electrons. It is also found that the entry of the ions into the gradient region causes phase bunching and as a result ion density striations form. The striations are enhanced for more abrupt changes in the electric field gradient, a weaker magnetic field, a stronger cross-tail electric field and colder O+ ions. The first two conditions apply during the growth phase of a substorm. Using the Tsyganenko (1987) model a minimum electric field gradient value of 1 x 1O(-9) V/m(2) ((1 mV/m)/1000 km) at L = 6-7 is found. Charge neutrality requires coupling with the ionosphere through electrons moving along magnetic held lines, and such electrons may be the cause of multiple auroral arcs.
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