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.
Highlights
The bladder exstrophy-epispadias complex (BEEC; OMIM %600057) is the most severe of all human congenital anomalies of the kidney and urinary tract (CAKUT), and involves the abdominal wall, pelvis, all of the urinary tract, the genitalia, and occasionally the spine and anus
The present study identified the first genome-wide significant locus for classic bladder exstrophy (CBE) at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region
The present genome-wide association study and meta-analysis identified an association between CBE and a region on chromosome 5q11.1
Summary
The bladder exstrophy-epispadias complex (BEEC; OMIM %600057) is the most severe of all human congenital anomalies of the kidney and urinary tract (CAKUT), and involves the abdominal wall, pelvis, all of the urinary tract, the genitalia, and occasionally the spine and anus. The recurrence risk for the offspring of CBE patients shows an approximate 400-fold increase compared to that observed in the general population [10]. Identification of genetic risk factors for the BEEC has been the subject of extensive recent research, and several lines of evidence support the hypothesis that genetic factors are implicated. These include reports of BEEC-associated chromosomal aberrations [13]; reports of at least 30 families with multiple affected members [13,14]; and observations of high concordance rates in monozygotic twins [5]. In the vast majority of cases, the genetic contribution to the BEEC remains elusive, and the molecular basis of the disruption of the respective developmental processes is poorly understood
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