An eQTL Landscape of Kidney Tissue in Human Nephrotic Syndrome.

Am J Hum Genet
Authors
Keywords
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 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."

Year of Publication
2018
Journal
Am J Hum Genet
Volume
103
Issue
2
Pages
232-244
Date Published
2018 08 02
ISSN
1537-6605
DOI
10.1016/j.ajhg.2018.07.004
PubMed ID
30057032
PubMed Central ID
PMC6081280
Links
Grant list
R01 DK105124 / DK / NIDDK NIH HHS / United States
R01 DK108805 / DK / NIDDK NIH HHS / United States
T32 HG000040 / HG / NHGRI NIH HHS / United States
U54 DK083912 / DK / NIDDK NIH HHS / United States