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

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 C lementsson Kockum, Nadine Zwink & 13 others Gundula Holmdahl, Göran Läckgren, Ekkehart Jenetzky, Wouter F J Feitz, Carlo Marcelis, Charlotte H W Wijers, Iris A L M Van Rooij, John Phillip Gearhart, Bernhard G. Herrmann, Michael Ludwig, Simeon A. Boyadjiev, Markus M. Nöthen, Manuel Mattheisen

Research output: Contribution to journalArticle

Abstract

Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal 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 cases/865 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 × 10(-5); follow-up: P = 0.0025; combined: 1.09 × 10(-6)) in a highly conserved 32 kb 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 (US)
Pages (from-to)5536-5544
Number of pages9
JournalHuman Molecular Genetics
Volume23
Issue number20
DOIs
StatePublished - Oct 15 2014

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Bladder Exstrophy
Intergenic DNA
Genome-Wide Association Study
Genome
Cohort Studies
Kidney
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

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Genome-wide association study and mouse expression data identify a highly conserved 32 kb 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.; Hirsch, Karin; Schmiedeke, Eberhard; Meesters, Christian; Becker, Tim; Stein, Raimund; Utsch, Boris; Mangold, Elisabeth; Nordenskjöld, Agneta; Barker, Gillian; Kockum, Christina C lementsson; Zwink, Nadine; Holmdahl, Gundula; Läckgren, Göran; Jenetzky, Ekkehart; Feitz, Wouter F J; Marcelis, Carlo; Wijers, Charlotte H W; Van Rooij, Iris A L M; Gearhart, John Phillip; Herrmann, Bernhard G.; Ludwig, Michael; Boyadjiev, Simeon A.; Nöthen, Markus M.; Mattheisen, Manuel.

In: Human Molecular Genetics, Vol. 23, No. 20, 15.10.2014, p. 5536-5544.

Research output: Contribution to journalArticle

Reutter, H, Draaken, M, Pennimpede, T, Wittler, L, Brockschmidt, FF, Ebert, AK, Bartels, E, Rösch, W, Boemers, TM, Hirsch, K, Schmiedeke, E, Meesters, C, Becker, T, Stein, R, Utsch, B, Mangold, E, Nordenskjöld, A, Barker, G, Kockum, CCL, Zwink, N, Holmdahl, G, Läckgren, G, Jenetzky, E, Feitz, WFJ, Marcelis, C, Wijers, CHW, Van Rooij, IALM, Gearhart, JP, Herrmann, BG, Ludwig, M, Boyadjiev, SA, Nöthen, MM & Mattheisen, M 2014, 'Genome-wide association study and mouse expression data identify a highly conserved 32 kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder', Human Molecular Genetics, vol. 23, no. 20, pp. 5536-5544. https://doi.org/10.1093/hmg/ddu259
Reutter, Heiko ; Draaken, Markus ; Pennimpede, Tracie ; Wittler, Lars ; Brockschmidt, Felix F. ; Ebert, Anne Karolin ; Bartels, Enrika ; Rösch, Wolfgang ; Boemers, Thomas M. ; Hirsch, Karin ; Schmiedeke, Eberhard ; Meesters, Christian ; Becker, Tim ; Stein, Raimund ; Utsch, Boris ; Mangold, Elisabeth ; Nordenskjöld, Agneta ; Barker, Gillian ; Kockum, Christina C lementsson ; Zwink, Nadine ; Holmdahl, Gundula ; Läckgren, Göran ; Jenetzky, Ekkehart ; Feitz, Wouter F J ; Marcelis, Carlo ; Wijers, Charlotte H W ; Van Rooij, Iris A L M ; Gearhart, John Phillip ; Herrmann, Bernhard G. ; Ludwig, Michael ; Boyadjiev, Simeon A. ; Nöthen, Markus M. ; Mattheisen, Manuel. / Genome-wide association study and mouse expression data identify a highly conserved 32 kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 20. pp. 5536-5544.
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abstract = "Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal 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 cases/865 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 × 10(-5); follow-up: P = 0.0025; combined: 1.09 × 10(-6)) in a highly conserved 32 kb 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.",
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T1 - Genome-wide association study and mouse expression data identify a highly conserved 32 kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder

AU - Reutter, Heiko

AU - Draaken, Markus

AU - Pennimpede, Tracie

AU - Wittler, Lars

AU - Brockschmidt, Felix F.

AU - Ebert, Anne Karolin

AU - Bartels, Enrika

AU - Rösch, Wolfgang

AU - Boemers, Thomas M.

AU - Hirsch, Karin

AU - Schmiedeke, Eberhard

AU - Meesters, Christian

AU - Becker, Tim

AU - Stein, Raimund

AU - Utsch, Boris

AU - Mangold, Elisabeth

AU - Nordenskjöld, Agneta

AU - Barker, Gillian

AU - Kockum, Christina C lementsson

AU - Zwink, Nadine

AU - Holmdahl, Gundula

AU - Läckgren, Göran

AU - Jenetzky, Ekkehart

AU - Feitz, Wouter F J

AU - Marcelis, Carlo

AU - Wijers, Charlotte H W

AU - Van Rooij, Iris A L M

AU - Gearhart, John Phillip

AU - Herrmann, Bernhard G.

AU - Ludwig, Michael

AU - Boyadjiev, Simeon A.

AU - Nöthen, Markus M.

AU - Mattheisen, Manuel

PY - 2014/10/15

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N2 - Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal 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 cases/865 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 × 10(-5); follow-up: P = 0.0025; combined: 1.09 × 10(-6)) in a highly conserved 32 kb 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.

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