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- 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. |
- Gahm, Gösta F., 1942-, et al.
(författare)
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Expanding shells around young clusters - S 171/Be 59
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 663
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Tidskriftsartikel (refereegranskat)abstract
- Context. Some HII regions that surround young stellar clusters are bordered by molecular shells that appear to expand at a rate inconsistent with our current model simulations. In this study we focus on the dynamics of Sharpless 171 (including NGC 7822), which surrounds the cluster Berkeley 59. Aims. We aim to compare the velocity pattern over the molecular shell with the mean radial velocity of the cluster for estimates of the expansion velocities of different shell structures, and to match the observed properties with model simulations. Methods. Optical spectra of 27 stars located in Berkeley 59 were collected at the Nordic Optical Telescope, and a number of molecular structures scattered over the entire region were mapped in 13CO(1- 0) at Onsala Space Observatory. Results. We obtained radial velocities and MK classes for the clustera's stars. At least four of the O stars are found to be spectroscopic binaries, in addition to one triplet system. From these data we obtain the mean radial velocity of the cluster. From the 13CO spectra we identify three shell structures, expanding relative to the cluster at moderate velocity (4 km s- 1), high velocity (12 km s- 1), and in between. The high-velocity cloudlets extend over a larger radius and are less massive than the low-velocity cloudlets. We performed a model simulation to understand the evolution of this complex. Conclusions. Our simulation of the Sharpless 171 complex and Berkeley 59 cluster demonstrates that the individual components can be explained as a shell driven by stellar winds from the massive cluster members. However, our relatively simple model produces a single component. Modelling of the propagation of shell fragments through a uniform interstellar medium demonstrates that dense cloudlets detached from the shell are decelerated less efficiently than the shell itself. They can reach greater distances and retain higher velocities than the shell.
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