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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.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
We derive a slip rate for a thrust at the central Qilian Shan mountain front by combining structural investigations, satellite imagery, topographic profiling, luminescence dating, and Be-10 exposure dating. The seismically active Zhangye thrust transects late Pleistocene alluvial fan deposits and forms a prominent north facing scarp. The fault consists of two segments that differ in orientation, scarp height, and age. A series of loess-covered terraces records the uplift history of the western thrust segment. Loess accumulation on all terraces started at 8.5 +/- 1.5 kyr and postdates terrace formation. Gravels from the highest terrace yielded a Be-10 exposure age of 90 +/- 11 kyr, which dates the onset of faulting. With a displacement of 55-60 m derived from fault scarp profiles, this yields a vertical slip rate of 0.64 +/- 0.08 mm yr(-1). Along the eastern thrust segment, three Be-10 ages from the uplifted alluvial fan constrain that faulting started at similar to31 +/- 5 kyr. Together with a displacement of 25-30 m this leads to a vertical faulting rate of 0.88 +/- 0.16 mm yr(-1). A dip estimate of 40degrees to 60degrees for the fault plane combined with lower and upper limits of similar to0.6 and similar to0.9 mm yr(-1) for the vertical slip rate gives minimum and maximum horizontal shortening rates of 0.4 and 1.1 mm yr(-1) across the Zhangye thrust. Our results are consistent with geologic and GPS constraints, which suggest that NNE directed shortening across the northeastern Tibetan Plateau is distributed on several active faults with a total shortening rate of 4 to 10 mm yr(-1)
A fault scaling law suggests that, over eight orders of magnitude, fault length L is linearly related to maximum displacement D. Individual faults may therefore retain a constant ratio of D/L as they grow. If erosion is minor compared with tectonic uplift, the length and along-strike relief of young mountain ranges should thus reflect fault growth. Topographic profiles along the crests of mountain ranges in the actively deforming foreland of north-east Tibet exhibit a characteristic shape with maximum height near their centre and decreasing elevation toward the tips. We interpret the along-strike relief of these ranges to reflect the slip distribution on high-angle reverse faults. A geometric model illustrates that the lateral propagation rate of such mountain ranges may be deciphered if their length- to-height ratio has remained constant. As an application of the model, we reconstruct the growth of the Heli Shan using a long-term uplift rate of similar to1.3 mm yr(-1) derived from Ne-21 and Be-10 exposure dating