title: 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.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Draaken
authors.affiliation: Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Tracie
authors.initials: T
authors.lastname: Pennimpede
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Schmidt
authors.affiliation: Department of Urology and Pediatric Urology, University Hospital of Ulm, Germany.
authors.forename: Anne-Karolin
authors.initials: AK
authors.lastname: Ebert
authors.affiliation: Department of Pediatric Urology, St. Hedwig Hospital Barmherzige Brüder, Regensburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rösch
authors.affiliation: Department of Urology, Division of Pediatric Urology, University of Mainz, Mainz, Germany.
authors.forename: Raimund
authors.initials: R
authors.lastname: Stein
authors.affiliation: Department of General Pediatrics and Neonatology, Justus Liebig University, Giessen, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Utsch
authors.affiliation: Department of Urology, Division of Paediatric Urology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Hirsch
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, Children's Hospital of Cologne, Cologne, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Boemers
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Ludwig
authors.affiliation: 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.
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Jenetzky
authors.affiliation: Department of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Zwink
authors.affiliation: Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Bernhard G
authors.initials: BG
authors.lastname: Herrmann
authors.affiliation: 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.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
mesh_terms: D000818:Animals; D001746:Bladder Exstrophy / Q000235:genetics*; D016022:Case-Control Studies; D055106:Genome-Wide Association Study; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1