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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.

Reutter, Heiko ; Draaken, Markus ; Pennimpede, Tracie ; Wittler, Lars ; Brockschmidt, Felix F ; Ebert, Anne-Karolin ; Bartels, Enrika ; Rösch, Wolfgang ; Boemers, Thomas M and Hirsch, Karin , et al. (2014) In Human Molecular Genetics 23(20). p.5536-5544
Abstract
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... (More)
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. (Less)
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@article{8e66e8e4-8c50-4a44-b94a-c814df4755de,
  abstract     = {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.},
  author       = {Reutter, Heiko and Draaken, Markus and Pennimpede, Tracie and Wittler, Lars and Brockschmidt, Felix F and Ebert, Anne-Karolin and Bartels, Enrika and Rösch, Wolfgang and Boemers, Thomas M and Hirsch, Karin and Schmiedeke, Eberhard and Meesters, Christian and Becker, Tim and Stein, Raimund and Utsch, Boris and Mangold, Elisabeth and Nordenskjöld, Agneta and Barker, Gillian and Clementson Kockum, Christina and Zwink, Nadine and Holmdahl, Gundula and Läckgren, Göran and Jenetzky, Ekkehart and Feitz, Wouter Fj and Marcelis, Carlo and Wijers, Charlotte H W and van Rooij, Iris A L M and Gearhart, John P and Herrmann, Bernhard G and Ludwig, Michael and Boyadjiev, Simeon A and Nöthen, Markus M and Mattheisen, Manuel},
  issn         = {0964-6906},
  language     = {eng},
  number       = {20},
  pages        = {5536--5544},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {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.},
  url          = {http://dx.doi.org/10.1093/hmg/ddu259},
  doi          = {10.1093/hmg/ddu259},
  volume       = {23},
  year         = {2014},
}