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Abstract: TH-PO706

A Genome-Wide Association Study Provides Insight into the Etiology of Congenital Obstructive Uropathy

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Lim, Tze Yin, Columbia University, New York, New York, United States
  • Ahram, Dina, Columbia University, New York, New York, United States
  • Westland, Rik, VU University Medical Center, Amsterdam, Netherlands
  • Verbitsky, Miguel, Columbia University, New York, New York, United States
  • Krithivasan, Priya, Columbia University, New York, New York, United States
  • Mitrotti, Adele, Columbia University, New York, New York, United States
  • Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy
  • Saraga, Marijan, University Hospital in Split, Split, Croatia
  • Ghiggeri, Gian Marco, Istituto Giannina Gaslini, Genoa, Italy
  • Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
  • Gesualdo, Loreto, University of Bari, Altamura, BARI, Italy
  • Gharavi, Ali G., Columbia University, New York, New York, United States
  • Kiryluk, Krzysztof, 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 frequent anomaly of the urinary tract. Human genetic and clinical data suggest that both rare and common genetic variants might be involved in the pathogenesis of COU.


We conducted SNP genotyping in 398 COU cases and 8197 controls on different Illumina platforms. Genome-wide association study (GWAS) was performed on two Caucasian cohorts of 280 cases (cohort 1) and 118 cases (cohort 2), divided based on platform. After standard QC we retained 444614 and 632574 markers in cohort 1 and cohort 2, respectively. We imputed these marker sets separately using the HRC1.1 panel. The results were meta-analyzed with METAL. Suggestive signals were cross-annotated with results from our exome-wide collapsing analysis for rare variants in 292 COU cases and 8541 controls.


Meta-analysis of the two cohorts (398 cases, 8197 controls and 7503796 markers) revealed 3 suggestive associations. The 1st was on chr4q26 (rs4833590; p=3.01x10-7) in SEC24D. A disruption of this gene causes embryonic lethality in mice, and mutations in humans are implicated in the Cole-Carpenter Syndrome-2 with no known urinary tract involvement. Other genes within 250Kb of this variant are CEP170P1, LOC729218, METTL14 and SYNPO2. The 2nd was on chr12q21 (rs10777060; p=9.98x10-6), 105.8kb upstream of BBS10, implicated in Bardet-Biedl syndrome, a ciliopathy with renal and urinary tract involvement. Neighboring genes are OSBPL8 and NAP1L1. A 3rd suggestive signal was on chr4q32 (rs6536312;p=9.70x10-6), 231.1kb upstream of ETFDH, a gene implicated in glutaric acidemia IIC, which features urogenital defects. Neighboring genes are TMEM144, RXFP1, C4orf46 and PPID. Cross-annotation with exome-wide collapsing analysis in 292 COU cases and 8541 controls showed evidence for enrichment in rare variants in BBS10 (p=3.2x10-3) and TMEM144 (p=1.2x10-2).


We present preliminary GWAS findings based on a relatively small sample size of 398 COU cases and identified 3 candidate loci. Integration with rare variants from an exome-wide association study permitted locus refinement and identification of novel susceptibility genes for follow-up studies in larger cohorts.


  • NIDDK Support