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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.
A geological transect across the suture separating northwestern South America from the Panama Arc helps document the provenance and thermal history of both crustal domains and the suture zone. During middle Miocene, strata were being accumulated over the suture zone between the Panama Arc and the continental margin. Integrated provenance analyses of those middle Miocene strata show the presence of mixed sources that includes material derived from the two major crustal domains: the old northwestern South American orogens and the younger Panama Arc. Coeval moderately rapid exhumation of Upper Cretaceous to Paleogene sediments forming the reference continental margin is suggested from our inverse thermal modeling. Strata within the suture zone are intruded by similar to 12 Ma magmatic arc-related plutons, marking the transition from a collisional orogen to a subduction-related one. Renewed late Miocene to Pliocene acceleration of the exhumation rates is the consequence of a second tectonic pulse, which is likely to be triggered by the onset of a flat-slab subduction of the Nazca plate underneath the northernmost Andes of Colombia, suggesting that late Miocene to Pliocene orogeny in the Northern Andes is controlled by at least two different tectonic mechanisms.