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Abstract: FR-OR19

Identification of Genes and Regulatory Elements Affecting Human Kidney Function

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Loeb, Gabriel, University of California San Francisco, San Francisco, California, United States
  • Kathail, Pooja, University of California Berkeley, Berkeley, California, United States
  • Shuai, Richard W., University of California Berkeley, Berkeley, California, United States
  • Chung, Ryan K., University of California Berkeley, Berkeley, California, United States
  • Grona, Reinier John, University of California San Francisco, San Francisco, California, United States
  • Peddada, Sailaja, Laboratory of Genomics Research/UCSF, San Francisco, California, United States
  • Sevim, Volkan, GSK plc, San Francisco, California, United States
  • Federman, Scot M., Laboratory of Genomics Research/UCSF, San Francisco, California, United States
  • Mader, Karl A., Laboratory of Genomics Research/UCSF, San Francisco, California, United States
  • Chu, Audrey Y., GSK plc, San Francisco, California, United States
  • Davitte, Jonathan M., GSK plc, San Francisco, California, United States
  • Shafer, Shawn L., GSK plc, San Francisco, California, United States
  • Przybyla, Laralynne, Laboratory of Genomics Research/UCSF, San Francisco, California, United States
  • Ioannidis, Nilah, University of California Berkeley, Berkeley, California, United States
  • Reiter, Jeremy, University of California San Francisco, San Francisco, California, United States
Background

The molecular mechanisms underlying human kidney disease remain largely unknown. Genome-wide association studies (GWAS) have identified hundreds of genomic loci associated with kidney function and disease. However, the genetic variants and genes mediating the effect of most of these loci remain unclear.

Methods

We performed a genome-wide association study (GWAS) of kidney function estimated using both creatinine and cystatin C in the UK Biobank and used functionally informed fine-mapping to identify putative causal kidney function variants. To determine the effect of genetic variants implicated in kidney function, we used scATAC-seq in human kidneys, genome-wide measurements of H3K27 acetylation (CUT&RUN), and measured the effect of CRISPR-mediated perturbation of regulatory elements on gene expression.

Results

We found that 58% of kidney function SNP-heritability localized to candidate regulatory elements of kidney tubule epithelial cells, an additional 6.5% localized to podocyte candidate regulatory elements, and <1% localized within endothelial, stromal, or immune cell-specific regulatory elements. We identified putative causal kidney function variants using functionally-informed fine-mapping and used these variants to identify regulatory elements and genes involved in kidney function. In human kidneys and primary tubule epithelial cells, we assessed how kidney function variants affect chromatin accessibility and enhancer function. We found that kidney function variants alter chromatin accessibility and enhancer function within tubule epithelial regulatory elements. A pooled screen targeting kidney function noncoding regulatory elements with CRISPR interference (CRISPRi) identified novel genes involved in human kidney function.

Conclusion

By integrating human genetics and studies of enhancer function, this work provides a framework for identifying variants, regulatory elements, and genes involved in human kidney disease. The combination of fine-mapping of GWAS-nominated variants, regulatory element identification, and mapping enhancers to regulated genes provides a framework for moving from GWAS to molecular mechanisms of disease.

Funding

  • NIDDK Support