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Abstract: TH-PO700

Exome-Wide Association Study Identifies Candidate Susceptibility Genes for Congenital Obstructive Uropathy

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Ahram, Dina, Columbia University, New York, New York, United States
  • Lim, Tze Yin, Columbia University, New York, New York, United States
  • Westland, Rik, VU University Medical Center, Amsterdam, Netherlands
  • Krithivasan, Priya, Columbia University, New York, New York, United States
  • Mitrotti, Adele, Columbia University, New York, New York, United States
  • Bodria, Monica, Istituto G. Gaslini, Genoa, Italy
  • Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy
  • Gesualdo, Loreto, University of Bari, Altamura, BARI, Italy
  • Saraga, Marijan, University Hospital in Split, Split, Croatia
  • Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Ghiggeri, Gian Marco, Istituto G. Gaslini, Genoa, Italy
  • Gharavi, Ali G., Columbia University, New York, New York, United States
  • Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Congenital Obstructive Uropathy (COU) is a cause of kidney failure in children. Monogenic forms of disease account for a small portion of cases. Rare variant association tests are promising approaches to identify novel disease genes.


We conducted exome sequencing in 292 COU cases and 8541 controls. Following diagnostic variant annotation in genes implicated in congenital anomalies of the kidney and urinary tract (CAKUT) using ACMG criteria, we searched for novel susceptibility COU genes using case-control exome-wide collapsing analyses for rare functional variants. We tested gene-level dominant and recessive models via fisher-exact statistics. Qualifying variants were selected using computational scores based on conservation and location in intolerant exons or conserved domains. We analyzed gene-set enrichment using 299 OMIM genes implicated in CAKUT in comparison to a control set of 857 olfactory genes. Finally,we cross-annotated suggestive signals with results from a GWAS for common variants consisting 398 cases and 8197 controls.


ACMG-based variant prioritization revealed pathogenic mutations in 11(3.7%) COU cases. Gene-level collapsing showed 20 genes with p<5x10-4 for dominant model (MAF<0.0005) and 2 genes for the recessive model (MAF<0.01),although no exome-wide significant signals (<2.5x10-6) were attained.Two candidate genes were particularly interesting: 1.MAZ (dominant missense model; p=3.58x10-5),a gene demonstrated to regulate urogenital development in a mouse model,and 2.FLNA (recessive model; p=4.25x10-5), a gene implicated in Otopalatodigital Spectrum Disorders,where hydronephrosis and megaureter were reported.Cross-annotation with GWAS signals revealed evidence for association of common variants to MAZ (p=7.06x10-3– 6.96x10-4).Gene set analysis for genes involved in kidney function showed enrichment for rare functional variant (χ2 = 9.12; p=2.5x10-3) compared to olfactory control genes (χ2=0.15; p=0.70) in cases versus controls.


This study addresses the contribution of rare and common variants under various genetic models to solve the etiology of COU.Preliminary results implicate both rare and common variants in MAZ as novel risk factors for COU.


  • NIDDK Support