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ASN / Education & Meetings / Kidney Week /
Abstract: TH-PO0163

Gene-Based Rare Variant Associations Identify Known and Candidate Loci in Polycystic Kidney Disease Across Population-Scale Cohorts

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

  • Elbarougy, Doaa E., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Yang, Hana, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • McDonnell, Shannon K., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Frank, Jacob A., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Azooz, Masara, A T Still University, Kirksville, Missouri, United States
  • Krivonos, Alexandra, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Al Qaderi, Maryam, Harvard University, Cambridge, Massachusetts, United States
  • Ma, Jun, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Cruz, Conrad, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Larson, Nicholas B., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background

PKD1 and PKD2 are the primary drivers of ADPKD, but ~8 additional minor loci have been identified. Large multi-ancestry gene-based studies can identify further minor genes, plus modifiers of disease severity.

Methods

We queried All of Us All-by-All gene-based rare variant association study (RVAS) results for cystic kidney phenotypes, including polycystic kidney disease (PKD), cystic kidney disease (CKD), and cyst of kidney (CoK). We additionally analyzed the Mayo Clinic Biobank (MCBB) and Tapestry cohorts, defining strict ADPKD and broader cystic phenotypes using ICD-based definitions. Analyses focused on pLoF (loss of function) burden tests (MAF≤0.001), and top-ranked genes were identified by gene-burden p-values.

Results

In All of Us, PKD (GE_976.5) showed strongest associations for PKD1, PKD2 and IFT140. For CKD (CM_761.13), PKD1, PKD2, IFT140, and PKHD1 showed the strongest associations. For the CoK (GU_586.2), which includes milder phenotypes, leading genes included IFT140, PKD1, and PKD2 (Table 1), with additional suggestive associations (CRISP1, ALG9, GANAB, COL4A4, CNRIP1, NEK8).
In addition, recurrent variants in these genes associated with the cystic phenotype were identified as strong candidates as disease modifiers. Phenome-wide association analysis (PheWAS) of IFT140 (as an example) showed that significant associations were restricted to kidney-related phenotypes (Figure 1).
In MCBB and Tapestry, PKD1 and PKD2 were the only significant genes across ADPKD and broader cystic phenotypes, with no additional loci reaching significance.

Conclusion

Gene-based RVAS identified multiple candidate loci for kidney cysts with cross-cohort validation. As expected, PKD1 and PKD2 were the strongest associations, but known minor genes and novel candidates were identified, plus single variants in known genes as possible disease modifiers. PheWAS can test whether kidney cysts are strongly associated with LoF variants.

Funding

  • NIDDK Support