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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.
Light and gravity are two key determinants in orientating plant stems for proper growth and development. The organization and dynamics of the actin cytoskeleton are essential for cell biology and critically regulated by actin-binding proteins. However, the role of actin cytoskeleton in shoot negative gravitropism remains controversial. In this work, we report that the actin-binding protein Rice Morphology Determinant (RMD) promotes reorganization of the actin cytoskeleton in rice (Oryza sativa) shoots. The changes in actin organization are associated with the ability of the rice shoots to respond to negative gravitropism. Here, light-grown rmd mutant shoots exhibited agravitropic phenotypes. By contrast, etiolated rmd shoots displayed normal negative shoot gravitropism. Furthermore, we show that RMD maintains an actin configuration that promotes statolith mobility in gravisensing endodermal cells, and for proper auxin distribution in light-grown, but not dark-grown, shoots. RMD gene expression is diurnally controlled and directly repressed by the phytochrome-interacting factor-like protein OsPIL16. Consequently, overexpression of OsPIL16 led to gravisensing and actin patterning defects that phenocopied the rmd mutant. Our findings outline a mechanism that links light signaling and gravity perception for straight shoot growth in rice.