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.
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.
Institute of Human Genetics Department of Neonatology, University of Bonn, Bonn, Germany reutter@uni-bonn.de mm@hum-gen.au.dk.
Heiko
H
Reutter
Institute of Human Genetics Department of Genomics, Life & Brain Center, Bonn, Germany reutter@uni-bonn.de mm@hum-gen.au.dk.
Markus
M
Draaken
Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Tracie
T
Pennimpede
Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Lars
L
Wittler
Institute of Human Genetics Department of Genomics, Life & Brain Center, Bonn, Germany.
Felix F
FF
Brockschmidt
Department of Urology and Pediatric Urology, University of Ulm, Ulm, Germany.
Anne-Karolin
AK
Ebert
Institute of Human Genetics.
Enrika
E
Bartels
Department of Pediatric Urology, St. Hedwig Hospital Barmherzige Brüder, Regensburg, Germany.
Wolfgang
W
Rösch
Department of Pediatric Surgery and Pediatric Urology, Children's Hospital of Cologne, Cologne, Germany.
Thomas M
TM
Boemers
Division of Paediatric Urology, Clinic of Urology, University of Erlangen-Nürnberg, Erlangen, Germany.
Karin
K
Hirsch
Department of Pediatric Surgery and Urology, Center for Child and Adolescent Health, Hospital Bremen-Mitte, Bremen, Germany.
Eberhard
E
Schmiedeke
Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
Christian
C
Meesters
Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Tim
T
Becker
Division of Pediatric Urology, University of Mainz, Mainz, Germany.
Raimund
R
Stein
Department of General Pediatrics and Neonatology, Center for Pediatric and Adolescent Care, Justus Liebig University, Gießen, Germany.
Boris
B
Utsch
Institute of Human Genetics.
Elisabeth
E
Mangold
Woman and Child Health, Karolinska Institutet, Stockholm, Sweden Department of Pediatric Surgery, Astrid Lindgren Children Hospital, Stockholm, Sweden.
Agneta
A
Nordenskjöld
Department of Women's and Children's Health, Pediatric Surgery, Uppsala University, Sweden.
Gillian
G
Barker
Department of Pediatric Surgery, University Hospital Lund, Lund, Sweden.
Christina Clementsson
CC
Kockum
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
Nadine
N
Zwink
Department of Pediatric Surgery, Queen Silvia Children's Hospital, Gothenburg, Sweden.
Gundula
G
Holmdahl
Section of Urology, Uppsala Academic Children Hospital, Uppsala, Sweden.
Göran
G
Läckgren
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.
Ekkehart
E
Jenetzky
Department of Urology, Pediatric Urology Center, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Wouter F J
WF
Feitz
Department of Genetics.
Carlo
C
Marcelis
Department for Health Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Charlotte H W
CH
Wijers
Department for Health Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Iris A L M
IA
Van Rooij
Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
John P
JP
Gearhart
Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Bernhard G
BG
Herrmann
Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
Michael
M
Ludwig
Section of Genetics, Department of Pediatrics, University of California Davis, Sacramento, USA.
Simeon A
SA
Boyadjiev
Institute of Human Genetics Department of Neonatology, University of Bonn, Bonn, Germany.
Markus M
MM
Nöthen
Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA Department of Genomic Mathematics, University of Bonn, Bonn, Germany Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Manuel
M
Mattheisen
D000818:Animals; D001483:Base Sequence; D001746:Bladder Exstrophy / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D017124:Conserved Sequence; D020022:Genetic Predisposition to Disease; D005835:Genitalia / Q000196:embryology / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism*; D060508:Wnt3 Protein / Q000235:genetics* / Q000378:metabolism*
C104146:SALL1 protein, human; D014157:Transcription Factors; C555507:WNT3 protein, human; C449090:WNT9B protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein