Abstract
Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
Highlights
Summary meta-analysis data for association between these SNPs and eGFR from 133,413 individuals was downloaded from the CKDGen Consortium[6]
Summary data for association between SNPs and gene expression was obtained from our ciseQTL analysis conducted in the TRANSLATE study/TCGA
We used three MR methods (robust inverse variance-weighted (IVW) method, penalised weighted median method and robust MR-Egger regression)[64] to estimate the causal effect of gene expression on eGFR
Summary
We found over-representation for our eGenes within HPA kidney-enriched genes when compared to all other kidney genes identified in the dataset (25% (75/305), vs 19% (3711/19,920), P = 0.0096 (Supplementary Data 2)) Taken together, these data suggest that the abundance of almost one in five genes expressed in the kidney is under genetic control of common variants in -cis. Several of the eGenes showed a ubiquitous pattern of abundance across renal cell clusters, while others were specific to one particular cellular lineages—that is, DPEP1 mapped exclusively to proximal tubule cells and TFDP2 was associated with cells of the ascending loop of Henle These findings provide evidence for the key role of CKD-dt GWAS SNPs in regulation of gene expression in the kidney.
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