Genome-wide association study and meta-analysis identify ISL1 as genome-wide significant susceptibility gene for bladder exstrophy

PLoS Genet. 2015 Mar 12;11(3):e1005024. doi: 10.1371/journal.pgen.1005024. eCollection 2015 Mar.

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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bladder Exstrophy / genetics*
  • Case-Control Studies
  • Genome-Wide Association Study*
  • Humans
  • LIM-Homeodomain Proteins / genetics*
  • LIM-Homeodomain Proteins / metabolism
  • Mice
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • LIM-Homeodomain Proteins
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1

Grant support

HR is supported by grant RE 1723/1-1 from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). MMN received support from the Alfried Krupp von Bohlen und Halbach-Stiftung, and is a member of the DFG-funded Excellence Cluster Immunosensation. Controls for our GWAS analyses were drawn from the Heinz Nixdorf Recall Study (HNR) cohort, which was established with the support of the Heinz Nixdorf Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.