An eQTL Landscape of Kidney Tissue in Human Nephrotic Syndrome

Nephrotic Syndrome Study Network (NEPTUNE)

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.”

Original languageEnglish (US)
Pages (from-to)232-244
Number of pages13
JournalAmerican Journal of Human Genetics
Volume103
Issue number2
DOIs
StatePublished - Aug 2 2018

Bibliographical note

Funding Information:
M.G.S. is supported by the Charles Woodson Clinical Research Fund, the Ravitz Foundation, and National Institutes of Health RO1-DK108805. K.K. is supported by National Institutes of Health RO1-DK105124. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research (ORDR), NCATS, and the National Institute of Diabetes, Digestive, and Kidney Diseases. RDCRN is an initiative of ORDR, NCATS. Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation.

Funding Information:
M.G.S. is supported by the Charles Woodson Clinical Research Fund , the Ravitz Foundation , and National Institutes of Health RO1-DK108805 . K.K. is supported by National Institutes of Health RO1-DK105124 . The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912 , is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Disease Clinical Research Network (RDCRN) , supported through a collaboration between the Office of Rare Diseases Research (ORDR) , NCATS , and the National Institute of Diabetes, Digestive, and Kidney Diseases . RDCRN is an initiative of ORDR, NCATS. Additional funding and/or programmatic support for this project has also been provided by the University of Michigan , NephCure Kidney International , and the Halpin Foundation .

Publisher Copyright:
© 2018 American Society of Human Genetics

Keywords

  • eQTL
  • expression quantitative trait loci
  • focal segmental glomerulosclerosis
  • genomics
  • glomerulus
  • kidney
  • minimal change disease
  • nephrotic syndrome
  • podocyte
  • proteinuria
  • single-cell RNA sequencing

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