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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.
Centroid moment tensor (CMT) parameters can be estimated from seismic waveforms. Since these data indirectly observe the deformation process, CMTs are inferred as solutions to inverse problems which are generally underdetermined and require significant assumptions, including assumptions about data noise. Broadly speaking, we consider noise to include both theory and measurement errors, where theory errors are due to assumptions in the inverse problem and measurement errors are caused by the measurement process. While data errors are routinely included in parameter estimation for full CMTs, less attention has been paid to theory errors related to velocity-model uncertainties and how these affect the resulting moment-tensor (MT) uncertainties. Therefore, rigorous uncertainty quantification for CMTs may require theory-error estimation which becomes a problem of specifying noise models. Various noise models have been proposed, and these rely on several assumptions. All approaches quantify theory errors by estimating the covariance matrix of data residuals. However, this estimation can be based on explicit modelling, empirical estimation and/or ignore or include covariances. We quantitatively compare several approaches by presenting parameter and uncertainty estimates in nonlinear full CMT estimation for several simulated data sets and regional field data of the M-1 4.4, 2015 June 13 Fox Creek, Canada, event. While our main focus is at regional distances, the tested approaches are general and implemented for arbitrary source model choice. These include known or unknown centroid locations, full MTs, deviatoric MTs and double-couple MTs. We demonstrate that velocity-model uncertainties can profoundly affect parameter estimation and that their inclusion leads to more realistic parameter uncertainty quantification. However, not all approaches perform equally well. Including theory errors by estimating non-stationary (non-Toeplitz) error covariance matrices via iterative schemes during Monte Carlo sampling performs best and is computationally most efficient. In general, including velocity-model uncertainties is most important in cases where velocity structure is poorly known.