Format

Send to

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

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

Author information

1
Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
2
Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
3
Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
4
Institute of Human Genetics, University of Bonn, Bonn, Germany.
5
Department of Urology and Pediatric Urology, University Hospital of Ulm, Germany.
6
Department of Pediatric Urology, St. Hedwig Hospital Barmherzige Brüder, Regensburg, Germany.
7
Department of Urology, Division of Pediatric Urology, University of Mainz, Mainz, Germany.
8
Department of General Pediatrics and Neonatology, Justus Liebig University, Giessen, Germany.
9
Department of Urology, Division of Paediatric Urology, University of Erlangen-Nürnberg, Erlangen, Germany.
10
Department of Pediatric Surgery and Pediatric Urology, Children's Hospital of Cologne, Cologne, Germany.
11
Department of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy, Johannes-Gutenberg University, Mainz, Germany.
12
Department of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
13
Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
14
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Genomic Mathematics, University of Bonn, Bonn, Germany.
15
Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
16
Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany.

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.

PMID:
25763902
PMCID:
PMC4357422
DOI:
10.1371/journal.pgen.1005024
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center