An eQTL Landscape of Kidney Tissue in Human Nephrotic Syndrome

Abstract

Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map these signals, eQTLBMA to discover GLOM- or TI-specific eQTLs, and single-cell RNA-seq data of control kidney tissue to identify the cell type specificity of significant eQTLs. We integrated eQTL data with an IgA Nephropathy (IgAN) GWAS to perform a transcriptome-wide association study (TWAS). We discovered 894 GLOM eQTLs and 1,767 TI eQTLs at FDR < 0.05. 14% and 19% of GLOM and TI eQTLs, respectively, had >1 independent signal associated with its expression. 12% and 26% of eQTLs were GLOM specific and TI specific, respectively. GLOM eQTLs were most significantly enriched in podocyte transcripts and TI eQTLs in proximal tubules. The IgAN TWAS identified significant GLOM and TI genes, primarily at the HLA region. In this study, we discovered GLOM and TI eQTLs, identified those that were tissue specific, deconvoluted them into cell-specific signals, and used them to characterize known GWAS alleles. These data are available for browsing and download via our eQTL browser, "nephQTL."

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

“…7). To further confirm these kidney-specific effects, we used gene expression data from manually micro-dissected human kidney compartments of 166 NEPTUNE participants 13 . We detected suggestive glomerular eQTL effects that were weak, but direction-consistent with GTEx for rs17831251 (Wald test P = 0.055) and rs17241973 (Wald test P = 0.024), wherein MN risk allele were associated with increased glomerular PLA2R1 mRNA levels ( Supplementary Fig.…”

“…9 and 11) 14 . To test for eQTL effects in kidney tissue, we used gene expression data from the NEPTUNE study 13 . This dataset is comprised of whole genome DNA sequence data and genome-wide transcriptome data (Affymetrix 2.1 ST chips) performed on microdissected glomerular (N = 136) and tubulointerstitial (N = 166) tissue compartments from kidney biopsies of patients with nephrotic syndrome.…”

“…For each locus, we tested the index SNP and its high LD SNPs (r 2 > 0.8). Testing for cis-eQTL effects involved all transcripts within 1-Mb region centred on each SNP using the additive linear regression with adjustments for age, sex, PEER factors and first 4 PCs of ancestry as described previously 13 . In addition to kidney tissue, all loci were similarly interrogated for eQTL effects in the GTEx database version 8.…”

The Genetic Architecture of Kidney Disease

“…Investigators can now make measurements in humans, human-derived cells, or biologic samples that can precisely define person-to-person differences in organelle function, the behavior and abundance of proteins, metabolites, or the level and pattern expression of genes. People are now determining not just the variation in the genome that controls clinical disease but also, more refined "endophenotypes," such as how variation throughout the genome affects the level of expression of genes in the kidney (7,8). As the fast pace of progress in the development of human-derived models, such as induced pluripotent stem cell-derived cells, kidney organoids, and kidneys on chips, continues, we will expand our ability to define phenotypes, including responses to various perturbations, in ways that we cannot with living humans (9,10).…”

Big science and big data in nephrology

“…Recent studies identified lysosomal beta A mannosidase (MANBA) as a potential target in CKD 47 and identified many genes involved in nephrotic syndrome. 48 Another expressionquantitative trait loci study separating glomeruli and tubules identified disabled-2 (DAB2), an adaptor in the transforming growth factor (TGF)-b pathway, as a key protein in CKD. 49…”