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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.
Geodetic and seismologic studies support a tectonic model for the central Himalaya wherein similar to 2 cm/yr of Indo-Asian convergence is accommodated along the primary decollement under the range, the Main Himalayan thrust. A steeper midcrustal ramp in the Main Himalayan thrust is commonly invoked as driving rapid rock uplift along a range-parallel band in the Greater Himalaya. This tectonic model, developed primarily from studies in central Nepal, is commonly assumed to project along strike with little lateral variation in Main Himalayan thrust geometry or associated rock uplift patterns. Here, we synthesize multiple lines of evidence for a major discontinuity in the Main Himalayan thrust in western Nepal. Analysis of topography and seismicity indicates that west of similar to 82.5 degrees E, the single band of steep topography and seismicity along the Main Himalayan thrust ramp in central Nepal bifurcates around a high-elevation, low-relief landscape, resulting in a two-step topographic front along an similar to 150 km segment of the central Himalaya. Although multiple models could explain this bifurcation, the full suite of data appears to be most consistent with a northward bend to the Main Himalayan thrust ramp and activation of a young duplex horse to the south. This poorly documented segmentation of the Main Himalayan thrust has important implications for the seismogenic potential of the western Nepal seismic gap and for models of the ongoing evolution of the orogen.