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Abstract: TH-PO357

Elucidating the Genetic Architecture of Cystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Sadeghi-Alavijeh, Omid, University College London Department of Renal Medicine, London, London, United Kingdom
  • Chan, Melanie M., University College London Department of Renal Medicine, London, London, United Kingdom
  • Gale, Daniel P., University College London Department of Renal Medicine, London, London, United Kingdom

Up to 15% of polycystic kidney disease (PKD) cases are unsolved, leading to an unmet clinical need. Using whole genome sequencing data provided by the 100,000 Genomes Project (100KGP), we sought to systematically characterise the genetic architecture of PKD.


We performed a sequencing-based genome-wide association study in 1,102 unrelated PKD patients and 20,088 ancestry-matched unaffected controls. The analysis was inclusive of individuals with diverse genetic ancestry. Enrichment of common, low-frequency (minor allele frequency [MAF] > 0.1%) and rare (MAF < 0.1%) single-nucleotide variant (SNV), indel and rare structural variant (SV) alleles on a genome-wide and per-gene basis was sought using a generalised linear mixed model approach to account for population structure.


Gene-based analysis of rare SNVs/indels predicted to be damaging revealed PKD1 (P=1.13x10-309), PKD2 (P=1.96x10-150), DNAJB11 (P=3.52x10-7) and COL4A3 (P=1.26x10-6) as significantly associated with the cystic phenotype. Depleting for “solved” cases led to the discovery of a significant association at IFT140 (P=3.46x10-17) and strengthening of the COL4A3 (P=9.27x10-7) association (Figure1), driven exclusively by heterozygous variants in both genes. After depleting for IFT140 and COL4A3 causative variants, no other genes were identified. Genome-wide analysis of over 18 million common and low-frequency variants did not reveal any statistically significant associations with disease.


These findings represent a thorough examination of the genetic architecture of a national PKD cohort using well-controlled statistical methodology. Causative monoallelic mutations in IFT140 have recently also been reported in other cohorts associated with a milder phenotype than PKD1/2-associated disease. The association with COL4A3 suggests that in some circumstances cystic kidney disease may be the presenting feature of type IV collagenopathy and further work is needed to understand the biological mechanism underlying this observation.

Figure 1 - Gene based Manhattan plot of the cystic cohort deplete for solved cases versus controls.


  • Other NIH Support