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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.
Schlemaite, with the simplified formula (Cu,rectangle)(6)(Pb,Bi)Se-4, is a new mineral species from the Niederschlema-Alberoda vein-type uranium deposit at Hartenstein, Erzgebirge, Germany. It occurs as anhedral to subhedral grains with no obvious forms or twinning, in aggregates of up to several hundred mum across, with berzelianite, eucairite and clausthalite in a dolomite-ankerite matrix. Schlemaite is black with a black streak and opaque with a metallic luster. It is brittle with an uneven fracture and no observable cleavage. It has a mean VHN (25 g load) of 106 kg/mm(2), which roughly equates to a Mobs hardness of 3. In plane-polarized reflected light, schlemaite is grey, non- pleochroic with a very weak bireflectance. It has very weak anisotropy, with rotation tints in shades of very pale metallic orange and blue, and shows no internal reflections. Electron-microprobe analyses yielded a mean composition Cu 38.86, Ag 2.57, An 0.07, Hg 0.09, Pb 13.75, Bi 9.12, Se 35.11, total 99.57 wt.%. The empirical formula (based on 4 Se apfu) is (Cu5.50Ag0.21)(Sigma5.71)(Pb0.60Bi0.39)(Sigma0.99)Se-4. The calculated density is 7.54 g/cm(3) (based on the empirical formula and unit-cell parameters refined from single-crystal data). Schlemaite is monoclinic, P2(1)/m, a 9.5341(8), b 4.1004(3), c 10.2546(8) Angstrom, beta 100.066(2)degrees, V 394.72(9) Angstrom(3), a:b:c 2.3252:1:2.5009, Z = 2. The crystal structure of schlemaite was solved by direct methods and refined to an R index of 4.8% using 1303 unique reflections collected on a four-circle diffractometer equipped with a CCD detector. The structure consists of intercalated ordered and disordered layers. The ordered layer consists of ladders of Ph2+ + Bi3+ coordinated by Se, the former showing strong lone-pair-stereoactive effects, and a network of Cu+ coordinated by Se anions. The disordered layer consists of an array of sites partly occupied by Cu+ and Ag+ in a variety of coordinations, and is characterized by strong short-range order. The strongest seven lines of the X-ray powder-diffraction pattern [d in Angstrom(I)(hkl)] are: 3.189(100)(012), 3.132(100)(112), 2.601(70)(113), 2.505(50)(311), 2.151(60)(014), 2.058(80)(020) and 1.909(50)(314). Although schlemaite is chemically similar to furutobeite, (Cu,Ag)(6)PbS4, it is not isostructural with it. The mineral is named after the Schlema-Alberoda uranium ore field near Schneeberg in the ancient mining region of Saxony, Germany
Understanding eastern African paleoclimate is critical for contextualizing early human evolution, adaptation, and dispersal, yet Pleistocene climate of this region and its governing mechanisms remain poorly understood due to the lack of long, orbitally-resolved, terrestrial paleoclimate records. Here we present leaf wax hydrogen isotope records of rainfall from paleolake sediment cores from key time windows that resolve long-term trends, variations, and high-latitude effects on tropical African precipitation. Eastern African rainfall was dominantly controlled by variations in low-latitude summer insolation during most of the early and middle Pleistocene, with little evidence that glacial-interglacial cycles impacted rainfall until the late Pleistocene. We observe the influence of high-latitude-driven climate processes emerging from the last interglacial (Marine Isotope Stage 5) to the present, an interval when glacial-interglacial cycles were strong and insolation forcing was weak. Our results demonstrate a variable response of eastern African rainfall to low-latitude insolation forcing and high-latitude-driven climate change, likely related to the relative strengths of these forcings through time and a threshold in monsoon sensitivity. We observe little difference in mean rainfall between the early, middle, and late Pleistocene, which suggests that orbitally-driven climate variations likely played a more significant role than gradual change in the relationship between early humans and their environment.