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Abstract: FR-OR070

Allele-Specific Expression Studies Identify Tubule Epithelial DACH1 as a Kidney Disease Gene

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Qiu, Chengxiang, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Yoson, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Shrestha, Rojesh, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Yang, Hongliu, West China Hospital of Sichuan University, Chengdu, SICHUAN, China
  • Pestell, Richard George, Pennsylvania cancer and regenerative medicine center, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Genome wide association analysis (GWAS) have identified significant associations between over 100 genetic loci and kidney disease development. However, finding causal genes, cell types and biological mechanisms underlying such associations remains a challenge. High throughput RNA-seq data allows transcriptome-wide scan of millions of variants and their impact on gene expression variation (eQTLs) in specific cells and tissues. Furthermore, incorporating allele-specific expression (ASE) analysis enables us to improve statistical power for such screening methods while controlling for biases and potential confounding factors.


We generated genotype and gene expression data of kidney tissue samples obtained from 121 healthy individuals of European descent. Additionally, we generated mice with tubule-specific dose reduction of Dach1 (Kspcre/Dach1flox/+). Kidney injury was studied in aging mice or following folic acid administration. We cultured primary renal tubule epithelial cells (TECs) from Dach1flox/+ mice for Cre adenovirus infection. Furthermore, we performed single cell RNA-sequencing on control and Kspcre/Dach1flox/flox mouse kidneys.


We identified 41 ASE loci (compared to 27 eQTL loci) with genome-wide significant associations to kidney function. Interestingly, kidney compartment-based ASE analysis identified a significant tubule-specific association between the CKD risk variant rs716877 genotype and DACH1 level, but not in glomeruli. The GWAS risk allele was associated with decreased DACH1 levels. By single cell RNA-sequencing analysis, we found that Dach1 is expressed in the loop of Henle, distal convoluted tubules and collecting ducts. Mice with reduced tubule-specific Dach1 level demonstrated worsened renal damage at baseline and following nephrotoxic injury. Reducing Dach1 expression in primary TECs directly increased profibrotic gene expression. Single cell RNA-sequencing analysis of Kspcre/Dach1flox/flox mice indicated a significantly increased expression level of proliferating tubule cells.


Combining ASE and GWAS integration analysis, we identified 41 putative causal associations between genetic variation and kidney development. In particular, we show that reducing tubule epithelial Dach1 level induces kidney fibrosis development via TEC proliferation.


  • NIDDK Support