Manuel Mattheisen

Genome-wide association study and mouse expression data identify a highly conserved 32kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder

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  • Heiko Reutter, Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Neonatology, University of Bonn, Bonn, Germany reutter@uni-bonn.de mm@hum-gen.au.dk.
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  • Markus Draaken, Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, Bonn, Germany.
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  • Tracie Pennimpede, Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany., Denmark
  • Lars Wittler, Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany., Denmark
  • Felix F Brockschmidt, Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, Bonn, Germany., Denmark
  • Anne-Karolin Ebert, Department of Urology and Pediatric Urology, University of Ulm, Ulm, Germany.
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  • Enrika Bartels, Institute of Human Genetics, University of Bonn, Bonn, Germany.
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  • Wolfgang Rösch, Department of Pediatric Urology, St. Hedwig Hospital Barmherzige Brüder, Regensburg, Germany.
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  • Thomas M Boemers, Department of Pediatric Surgery and Pediatric Urology, Children's Hospital of Cologne, Cologne, Germany., Denmark
  • Karin Hirsch, Division of Paediatric Urology, Clinic of Urology, University of Erlangen-Nürnberg, Erlangen, Germany., Denmark
  • Eberhard Schmiedeke, Department of Pediatric Surgery and Urology, Center for Child and Adolescent Health, Hospital Bremen-Mitte, Bremen, Germany.
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  • Christian Meesters, Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
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  • Tim Becker, Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
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  • Raimund Stein, Division of Pediatric Urology, University of Mainz, Mainz, Germany., Denmark
  • Boris Utsch, Department of General Pediatrics and Neonatology, Center for Pediatric and Adolescent Care, Justus Liebig University, Gießen, Germany., Denmark
  • Elisabeth Mangold, Institute of Human Genetics, University of Bonn, Bonn, Germany.
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  • Agneta Nordenskjöld, Woman and Child Health, Karolinska Institutet, Stockholm, Sweden Department of Pediatric Surgery, Astrid Lindgren Children Hospital, Stockholm, Sweden., Denmark
  • Gillian Barker, Department of Women's and Children's Health, Pediatric Surgery, Uppsala University, Sweden., Denmark
  • Christina Clementsson Kockum, Lund University, Denmark
  • Nadine Zwink, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany., Denmark
  • Gundula Holmdahl, Department of Pediatric Surgery, Queen Silvia Children's Hospital, Gothenburg, Sweden., Denmark
  • Göran Läckgren, Section of Urology, Uppsala Academic Children Hospital, Uppsala, Sweden., Denmark
  • Ekkehart Jenetzky, Division 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., Denmark
  • Wouter Fj Feitz, Department of Urology, Pediatric Urology Center, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands., Denmark
  • Carlo Marcelis, Department of Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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  • Charlotte H W Wijers, Department for Health Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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  • Iris A L M van Rooij, Department for Health Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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  • John P Gearhart, Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
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  • Bernhard G Herrmann, Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany., Denmark
  • Michael Ludwig, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
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  • Simeon A Boyadjiev, Section of Genetics, Department of Pediatrics, University of California Davis, Sacramento, USA.
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  • Markus M Nöthen, Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Neonatology, University of Bonn, Bonn, Germany.
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  • Manuel Mattheisen

Bladder Exstrophy-Epispadias Complex (BEEC), the severe end of the uro-rectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218/865 cases/controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P=8.88 x 10(-5); follow-up: P=0.0025; combined: 1.09 x 10(-6)) in a highly conserved 32kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P=0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.

Original languageEnglish
JournalHuman Molecular Genetics
ISSN0964-6906
DOIs
Publication statusPublished - 22 May 2014

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