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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
The structure of the coronal magnetic field prior to eruptive processes and the conditions for the onset of eruption are important issues that can be addressed through studying the magnetohydrodynamic (MHD) stability and evolution of nonlinear force-free field (NLFFF) models. This paper uses data-constrained NLFFF models of a solar active region (AR) that erupted on 2010 April 8 as initial conditions in MHD simulations. These models, constructed with the techniques of flux rope insertion and magnetofrictional relaxation (MFR), include a stable, an approximately marginally stable, and an unstable configuration. The simulations confirm previous related results of MFR runs, particularly that stable flux rope equilibria represent key features of the observed pre-eruption coronal structure very well, and that there is a limiting value of the axial flux in the rope for the existence of stable NLFFF equilibria. The specific limiting value is located within a tighter range, due to the sharper discrimination between stability and instability by the MHD description. The MHD treatment of the eruptive configuration yields a very good agreement with a number of observed features, like the strongly inclined initial rise path and the close temporal association between the coronal mass ejection and the onset of flare reconnection. Minor differences occur in the velocity of flare ribbon expansion and in the further evolution of the inclination; these can be eliminated through refined simulations. We suggest that the slingshot effect of horizontally bent flux in the source region of eruptions can contribute significantly to the inclination of the rise direction. Finally, we demonstrate that the onset criterion, formulated in terms of a threshold value for the axial flux in the rope, corresponds very well to the threshold of the torus instability in the considered AR.