Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases
Yong Li, et al.
Yong Li, et al.
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Research Article Genetics Nephrology

Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases

Abstract

Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin’s complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.

Authors

Yong Li, Yurong Cheng, Francesco Consolato, Guglielmo Schiano, Michael R. Chong, Maik Pietzner, Ngoc Quynh H. Nguyen, Nora Scherer, Mary L. Biggs, Marcus E. Kleber, Stefan Haug, Burulça Göçmen, Marie Pigeyre, Peggy Sekula, Inga Steinbrenner, Pascal Schlosser, Christina B. Joseph, Jennifer A. Brody, Morgan E. Grams, Caroline Hayward, Ulla T. Schultheiss, Bernhard K. Krämer, Florian Kronenberg, Annette Peters, Jochen Seissler, Dominik Steubl, Cornelia Then, Matthias Wuttke, Winfried März, Kai-Uwe Eckardt, Christian Gieger, Eric Boerwinkle, Bruce M. Psaty, Josef Coresh, Peter J. Oefner, Guillaume Pare, Claudia Langenberg, Jürgen E. Scherberich, Bing Yu, Shreeram Akilesh, Olivier Devuyst, Luca Rampoldi, Anna Köttgen

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Figure 2

Functional genomic annotation of significantly associated independent variants at the UMOD/PDILT locus using gene expression and chromatin accessibility data from primary human kidney.

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Functional genomic annotation of significantly associated independent va...
The upper part shows the regional association plot of the UMOD/PDILT locus, using the 2 independent variants as reference SNPs. For nonreference SNPs, the extent of linkage disequilibrium (LD) with the reference SNP with higher correlation is shown by color gradients. Genetic positions (x axis) represent GRCh38 coordinates. Open chromatin peaks in different kidney cell type tracks based on single nuclear (sn)ATAC-Seq are shown underneath the regional association plot. Gene expression and open chromatin tracks of cortex (light blue tracks) and medulla (dark green tracks) based on bulk RNA-Seq and ATAC-Seq are shown in the lower part as density peaks. SNPs in the 2 independent credible sets with posterior probability (PP) > 0.01 are marked by ticks (purple) and the 10 kb windows encompassing them by the black horizontal bars. Hi-C data generated from kidney cortex was analyzed for contacts (orange arcs) between the 10 kb windows encompassing the indicated SNPs with contacts closest to the causal SNPs arbitrarily shown in bold. Intervals for DomainCaller computed topology associated domains (TADs) are shown as black bars below contact arcs. A heatmap of all Hi-C contacts encompassing this region is shown at the bottom (purple). Podo, podocyte; PT, proximal tubule; LOH, loop of Henle; DCT, distal convoluted tubule; CDPC, collecting duct principal cells; CDIC, collecting duct intercalated cells.