Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy

Abstract

The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10−12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.

Translational Research for Pediatric Lower Urinary Tract Dysfunction

“…Since they are major anomalies caused by defective urorectal development, they have recently drawn the attention of basic scientists [50-52]. For bladder exstrophy, a genome-wide association study followed by a whole exome sequencing study revealed the importance of the ISL1-pathway in humans and mice and proposed SLC20A1 and CELSR3 as candidate genes [51,52]. For cloacal anomalies, comparative genomic hybridization revealed CNVs in 7 patients (41%), including 5 gains and 2 losses [50].…”

Epispadias and the associated embryopathies: genetic and developmental basis

“…Interpretation of Bmp signals in Isl1 cell lineages is one of the critical developmental processes in GT and pelvic organ formation. Disruption of Bmp signal in such Isl1 lineages leads to the defective caudal midline regions (41,45). Such phenotypes mimic agenesis of the corresponding region representing a model for mermaid syndrome (41).…”

Clinical and risk factor analysis of cloacal defects in the National Birth Defects Prevention Study

“…An unpublished whole exome sequencing study in six CE child‐parent trios performed through the Center for Mendelian Genomics at the University of Washington did not reveal any plausible candidate genes (Keegan et al, unpublished). Additionally, the few candidate gene and genome‐wide association studies performed to date on the bladder exstrophy‐epispadias complex (BEEC)—which includes BE, PC, and CE—reported several potential candidate genes, including ISL1 (Draaken et al, ), p63 (Qi et al, ; Wilkins et al, ), and WNT3 (Reutter et al, ).…”