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Abstract: PO1722

Kidney Transcriptome-Wide Association Study Analysis Identifies Dach1 as a Kidney Disease Risk Gene

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Doke, Tomohito, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Qiu, Chengxiang, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sheng, Xin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Zhou, Jianfu, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Cao, Aili, Icahn School of Medicine at Mount Sinai, New York, United States
  • Li, Jianhua, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Kaufman, Lewis, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Pestell, Richard George, Pennsylvania Cancer and Regenerative Medicine Research Center, Doylestown, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Genome-wide association studies (GWAS) has identified more than 300 loci where genetic variants are associated with kidney function, however, the causal variants, genes, cell types and the disease mechanism remain mostly unknown. Transcriptome-wide association studies (TWAS) is a method to prioritize GWAS-identified variants by linking gene expression data to phenotypic and genetic variation.

Methods

We obtained genotype and gene expression data for 121 microdissected human kidney tubule and glomerular samples. We applied a variety of TWAS models, such as Mendelian Randomization, TWAS Fusion, Metaxcan. Bulk kidney epigenome maps and single cell ATAC-Seq data were used for fine-mapping. We generated tubule specific Dach1 knock-out (KspCre/Dach1flox/flox) and transgenic (Pax8-TREDach1) mice to define the functional role of Dach1 in kidney disease development. Murine cultured tubule cells and single cell RNA sequencing were used for functional studies.

Results

Integration of the 3 TWAS methods with CKD GWAS datasets highlighted only 5 genes those levels were consistently influenced by the GWAS variants. Expression of DACH1; a transcription factor, was lower in tubules of patients with CKD risk variant. Immunofluorescence analysis indicated that DACH1 was mainly expressed in podocytes and in distal convoluted tubule (DCT) in the kidney. Bulk and single cell ATAC denoted that disease risk variants localized to a regulatory region in the DCT. Mice with tubule specific Dach1 deletion developed more severe renal fibrosis when challenged with folic acid (FA) compared to controls. Mice with tubule specific Dach1 overexpression were protected from FAN-induced kidney fibrosis. Single cell RNA sequencing and cultured primary renal tubule cells indicated that Dach1 plays role in controlling cell proliferation and inflammatory gene expression contributing to fibrosis development.

Conclusion

Integration of GWAS, TWAS, single cell expression, epigenome analysis, mouse models and cultured cell systems identified Dach1 as a causal gene for CKD.

Funding

  • NIDDK Support