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Sökning: WFRF:(Murakami N) > Umeå universitet

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1.
  • Mishra, A., et al. (författare)
  • Stroke genetics informs drug discovery and risk prediction across ancestries
  • 2022
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
  • 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.
  • Willems, S. M., et al. (författare)
  • Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
  • 2017
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality. © The Author(s) 2017.
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3.
  • Aizawa, S., et al. (författare)
  • Cross-comparison of global simulation models applied to Mercury's dayside magnetosphere
  • 2021
  • Ingår i: Planetary and Space Science. - : Elsevier. - 0032-0633 .- 1873-5088. ; 198
  • Tidskriftsartikel (refereegranskat)abstract
    • We present the first comparison of multiple global simulations of the solar wind interaction with Mercury's dayside magnetosphere, conducted in the framework of the international collaborative project SHOTS - Studies on Hermean magnetosphere Oriented Theories and Simulations. Two 3D magnetohydrodynamic and two 3D hybrid simulation codes are used to investigate the global response of the Hermean magnetosphere without its exosphere to a northward-oriented interplanetary magnetic field. We cross-compare the results of the four codes for a theoretical case and a MESSENGER orbit with similar upstream plasma conditions. The models agree on bowshock and magnetopause locations at 2.1 ​± ​0.11 and 1.4 ​± ​0.1 Mercury planetary radii, respectively. The latter locations may be influenced by subtle differences in the treatment of the plasma boundary at the planetary surface. The predicted magnetosheath thickness varies less between the codes. Finally, we also sample the plasma data along virtual trajectories of BepiColombo's Magnetospheric and Planetary Orbiter. Our ability to accurately predict the structure of the Hermean magnetosphere aids the analysis of the onboard plasma measurements of past and future magnetospheric missions.
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  • Resultat 1-3 av 3

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