Genetic Analysis of Two Bladder Exstrophy Populations of South Asian and European Origin
Austin Thompson, BA1, John K. Weaver, MD1, Dana A. Weiss, MD2, Neeta D’Souza, BS2, Rakesh Joshi, MD3, Jaishri Ramji, MD3, Aseem R. Shukla, MD2, Reiley Broms, BS2, Joseph Glessne, PhD2, Frank Mentch, PhD2, Hakon Hakonarson, MD2, Louise C. Pyle, MD4.
1Division of Urology Rainbow Babies and Children's Hospital/Case Western Reserve University School of Medicine, Cleveland, OH, USA, 2Division of Urology Children's Hospital of Philadelphia, Philadelphia, PA, USA, 3Civil Hospital, Ahmedabad, India, 4Center for Genetic Medicine Research Children’s National Hospital, Washington, DC, USA. Background
Bladder exstrophy-epispadias complex (BEEC) is a continuum of diseases, including bladder exstrophy, a complex congenital disorder of the urinary tract associated with an increased risk for bladder cancer. While the etiology is unknown, a genetic component is evident. Close to twenty cases of twins have been reported, and parents who have previously given birth to a child with BEEC have a 400 times greater risk than the general population of having another child with BEEC. Currently, the BE literature is limited to a European background. Here, we hypothesized that our genetically unique South Asian population would provide a rare opportunity for gene discovery with implications for understanding the genetic mechanisms responsible for BEEC.
METHODS
Our study includes two genetically unique cohorts. Following IRB approval and parental consent, DNA was isolated from peripheral blood samples and biobanked from our European and South Asian cohorts. Controls for both cohorts were identified from our institute's Center for Applied Genomics via health record mining for BEEC-negative individuals and subsequent ethnicity matching by principal component analysis. DNA collected from the European cohort was genotyped via a variety of different arrays, while DNA collected from the South Asian cohort was genotyped using the Illumina Global Screening Array. Related individuals and duplicates were removed using identity-by-state (PLINK). CNVs calling was achieved with PennCNV. All CNV-regions with p-values <0.05 were filtered using ParseCNV.
Results
A combined analysis of the cohorts identified 38 CNVs of statistical significance. See Table 1 and Table 2 for a full list of CNV duplications and CNV deletions, respectively. When analyzed individually, 3 and 16 additional CNVs were significant within the South Asian and European cohorts, respectively. None of our identified CNVs were in linkage disequilibrium with previously reported BEEC GWAS loci. We identified two previously reported CNVs, chr9:136131539-136131651 and chr9:137294228-137308636. One CNV, chr16: 28635133-28636902, was located near a previously reported CNV of clinical significance. Ten of 23 duplication CNVs and 6/18 deletion CNVs included genes implicated in cancer development (Table 3).
Conclusions
We present the first genetic analysis of a non-European cohort of 93 BE patients. We identified 36 novel CNVs, with a high proportion of CNVs containing genes with known cancer associations, some distinct from previously identified genes in European cohorts. The insights gained from our South Asian cohort will expand our knowledge beyond the previously restricted European background, making it more applicable to multiple geo-ethnic populations. These findings will also serve as the foundation for further genetic analysis through genome-wide
association, whole-genome, comparison to familial controls, and collaboration for meta-analysis with other cohorts.
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