Abstract: FR-OR067
Copy Number Variation and Genome-Wide Association Studies Identify Risk Loci with Large Effects on Vesicoureteral Reflux
Session Information
- Genetic Diseases and the Kidneys
November 08, 2019 | Location: 144, Walter E. Washington Convention Center
Abstract Time: 05:42 PM - 05:54 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Verbitsky, Miguel, Columbia University, New York, New York, United States
- Krithivasan, Priya, Columbia University, New York, New York, United States
- Marasa, Maddalena, Columbia University , New York, New York, United States
- Kil, Byum hee, Columbia University , New York, New York, United States
- Mitrotti, Adele, Columbia University , New York, New York, United States
- Sampson, Matt G., University of Michigan, Ann Arbor, Michigan, United States
- Bodria, Monica, Istituto G. Gaslini, Genoa, Italy
- Shril, Shirlee, Boston Childrens Hospital, Boston, Massachusetts, United States
- Gesualdo, Loreto, University of Bari, Altamura, Bari, Italy
- Masnata, Giuseppe, Azienda Ospedale G. Brotzu, Cagliari, Italy
- Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy
- Westland, Rik, VU University Medical Center, Amsterdam, Netherlands
- Van Wijk, Joanna, Vrije Universiteit University Hospital Amsterdam, Amsterdam, Netherlands
- Saraga, Marijan, University Hospital in Split, Split, Croatia
- Santoro, Domenico, Policlinico G Martino, Messina, Italy
- Zamboli, Pasquale, Second University of Naples, Naples, Italy
- Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
- Wong, Craig S., UNM, Albuquerque, New Mexico, United States
- Fiaccadori, Enrico, Universita Degli Studi-Dip. Clinica Medica Nefrologia, Parma, Italy
- Lin, Fangming, Columbia University College of Physicians & Surgeons, New York, New York, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Kiryluk, Krzysztof, Columbia University, New York, New York, United States
- Mendelsohn, Cathy, Columbia University Medical Center, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
- Gharavi, Ali G., Columbia University , New York, New York, United States
Background
Vesicoureteral reflux (VUR) is a highly familial disease caused by malfunction of the vesicoureteral junction, resulting in retrograde flow of urine from the bladder into the ureters and kidney and accounts for 25-30% of pediatric ESRD worldwide. Very few genetic risk factors for VUR have been identified to date.
Methods
We undertook a Copy Number Variant (CNV) study on 1,737 VUR cases compared to 24,765 controls and GWAS on 1,395 unrelated VUR cases of European ancestry and 5,366 matched population controls, under additive, recessive and dominant models; we also performed sex-specific analyses.
Results
We found a significant excess of large, rare gene-intersecting CNVs in VUR cases (P = 1.87 x 10-7). We identified distinct known pathogenic CNV in 35 (2.01%) of cases vs. 0.65% of controls (OR = 3.12; 95% CI = 2.10 - 4.54; P = 6.35 x 10-8). The VUR cases were enriched for 1q21.1 deletions, 16p11.2 deletions, 22q11.21 deletions and duplications, and triple X syndrome.
Our GWAS identified 3 study-wide significant (P<7.58 x 10-9) and 5 suggestive (P<1.52 x 10-7) loci with large effects (ORs = 1.41 to 3.65). The top SNPs for each of these associations were within or near genes known to be important in embryonic development and/or kidney disease (WDPCP, OTX1, BMP5, WNT5A, VANGL1). In addition, we estimated genetic heritability to be 15% based on the additive model results from all SNPs tested, and 4% based on a genotypic risk score from only the top 8 signals from all models. In situ hybridization confirmed that the top candidate genes are expressed in the ureter or vesicoureteral junction during mouse genitourinary development.
Conclusion
This study identifies multiple rare CNV disorders and common variants which impart large effects on the risk of VUR and implicate multiple canonical developmental pathways in the pathogenesis of disease.
Funding
- NIDDK Support