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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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Author

  • Heiko Reutter
  • Markus Draaken
  • Tracie Pennimpede
  • Lars Wittler
  • Felix F Brockschmidt
  • Anne-Karolin Ebert
  • Enrika Bartels
  • Wolfgang Rösch
  • Thomas M Boemers
  • Karin Hirsch
  • Eberhard Schmiedeke
  • Christian Meesters
  • Tim Becker
  • Raimund Stein
  • Boris Utsch
  • Elisabeth Mangold
  • Agneta Nordenskjöld
  • Gillian Barker
  • Christina Clementson Kockum
  • Nadine Zwink
  • Gundula Holmdahl
  • Göran Läckgren
  • Ekkehart Jenetzky
  • Wouter Fj Feitz
  • Carlo Marcelis
  • Charlotte H W Wijers
  • Iris A L M van Rooij
  • John P Gearhart
  • Bernhard G Herrmann
  • Michael Ludwig
  • Simeon A Boyadjiev
  • Markus M Nöthen
  • Manuel Mattheisen
Show all

Summary, in English

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.

Department/s

Publishing year

2014

Language

English

Pages

5536-5544

Publication/Series

Human Molecular Genetics

Volume

23

Issue

20

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Medical Genetics

Status

Published

ISBN/ISSN/Other

  • ISSN: 0964-6906