Abstract
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
Highlights
Genetic association results are freely available on the CKDGen Consortium website [https://ckdgen.imbi.uni-freiburg.de/]
For this lookup, all pQTLs with p < 1 × 10−4 were selected
Summary
The workflow of our study, which identified 68 UACR-associated loci across primary and secondary analyses, is illustrated in Supplementary Fig. 1. Co-localization of UACR association signals with those for pQTLs of 38 proteins (Methods, Supplementary Table 5) provided evidence for a shared underlying SNP for plasma concentrations of the Out At First Homolog (OAF) protein This was consistent with the eQTL co-localization analyses, with the minor T allele at rs12790943 associated with higher levels of UACR as well as with both lower OAF transcript levels in multiple tissues and lower OAF plasma levels (Fig. 7). The SNP rs508205 is located upstream of OAF, and was the index variant identified in the trans-ethnic meta-analysis of UACR (r2 = 0.94 with rs12790943 in the 1000 Genomes Project EUR sample) It represents an interesting regulatory candidate variant because of its relatively small credible set of eight SNPs, a CADD score of 13, and its localization in open chromatin in kidney tissue. The Drosophila data support a role of OAF in tubular protein endocytosis and PRKCI in slit diaphragm formation
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