Kidney Week

Abstract: TH-PO706

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

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Lim, Tze Yin, Columbia University, New York, New York, United States

Tze Yin Lim,

• Ahram, Dina, Columbia University, New York, New York, United States

Dina Ahram,

• Westland, Rik, VU University Medical Center, Amsterdam, Netherlands

Rik Westland,

• Verbitsky, Miguel, Columbia University, New York, New York, United States

Miguel Verbitsky,

• Krithivasan, Priya, Columbia University, New York, New York, United States

Priya Krithivasan,

• Mitrotti, Adele, Columbia University, New York, New York, United States

Adele Mitrotti,

• Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy

Francesco Scolari,

• Saraga, Marijan, University Hospital in Split, Split, Croatia

Marijan Saraga,

• Ghiggeri, Gian Marco, Istituto Giannina Gaslini, Genoa, Italy

Gian Marco Ghiggeri,

• Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)

Velibor Tasic,

• Gesualdo, Loreto, University of Bari, Altamura, BARI, Italy

Loreto Gesualdo,

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi,

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk,

• Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Simone Sanna-Cherchi,

Background

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.

Methods

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.

Results

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).

Conclusion

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.

Funding

• NIDDK Support