. 2022 Nov 9;5(1):1203.

doi: 10.1038/s42003-022-04092-3.

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Enrico Mingardo^#^{1

2

3}, Glenda Beaman^#⁴, Philip Grote^#^{5

6}, Agneta Nordenskjöld^{7

8}, William Newman⁴, Adrian S Woolf^{9

10}, Markus Eckstein^{11

12

13}, Alina C Hilger^{14

15}, Gabriel C Dworschak^{16

14}, Wolfgang Rösch¹⁷, Anne-Karolin Ebert¹⁸, Raimund Stein¹⁹, Alfredo Brusco²⁰, Massimo Di Grazia²¹, Ali Tamer⁵, Federico M Torres²², Jose L Hernandez²³, Philipp Erben^{13

24}, Carlo Maj²⁵, Jose M Olmos²⁶, Jose A Riancho²⁶, Carmen Valero²⁶, Isabel C Hostettler^{27

28

29}, Henry Houlden²⁸, David J Werring³⁰, Johannes Schumacher³¹, Jan Gehlen³¹, Ann-Sophie Giel³¹, Benedikt C Buerfent³¹, Samara Arkani^{32

33}, Elisabeth Åkesson^{34

35}, Emilia Rotstein³⁶, Michael Ludwig³⁷, Gundela Holmdahl³⁸, Elisa Giorgio^{39

40}, Alfredo Berettini⁴¹, David Keene⁴², Raimondo M Cervellione⁴², Nina Younsi¹⁹, Melissa Ortlieb¹⁸, Josef Oswald⁴³, Bernhard Haid^{19

43}, Martin Promm¹⁷, Claudia Neissner¹⁷, Karin Hirsch⁴⁴, Maximilian Stehr⁴⁵, Frank-Mattias Schäfer^{45

46}, Eberhard Schmiedeke⁴⁷, Thomas M Boemers⁴⁸, Iris A L M van Rooij⁴⁹, Wouter F J Feitz⁵⁰, Carlo L M Marcelis⁵¹, Martin Lacher⁵², Jana Nelson⁵², Benno Ure⁵³, Caroline Fortmann⁵³, Daniel P Gale⁵⁴, Melanie M Y Chan⁵⁴, Kerstin U Ludwig¹⁴, Markus M Nöthen¹⁴, Stefanie Heilmann^{14

55}, Nadine Zwink⁵⁶, Ekkehart Jenetzky^{56

57}, Benjamin Odermatt^{16

58}, Michael Knapp^#⁵⁹, Heiko Reutter^#^{60

61}

Affiliations

¹ Institute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany. enming@uni-bonn.de.
² Institute for Neuroanatomy, University Hospital Bonn, University of Bonn, Bonn, Germany. enming@uni-bonn.de.
³ Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany. enming@uni-bonn.de.
⁴ Centre for Genomic Medicine, University of Manchester, Manchester, UK.
⁵ Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.
⁶ Georg-Speyer-Haus, Frankfurt am Main, Germany.
⁷ Department of Women´s and Children´s Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.
⁹ Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, UK.
¹⁰ Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
¹¹ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
¹² Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany.
¹³ BRIDGE-Consortium Germany e.V., Mannheim, Germany.
¹⁴ Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany.
¹⁵ Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.
¹⁶ Institute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany.
¹⁷ Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center of Regensburg, Regensburg, Germany.
¹⁸ Department of Urology and Pediatric Urology, University Hospital of Ulm, Ulm, Germany.
¹⁹ Center for Pediatric, Adolescent and Reconstructive Urology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
²⁰ Department of Medical Sciences and Medical Genetics Unit, Città della Salute e della Scienza University Hospital, University of Torino, Torino, Italy.
²¹ Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy.
²² Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
²³ Department of Internal Medicine, Hospital U M Valdecilla, University of Cantabria, IDIVAL, Santander, Spain.
²⁴ Department of Urology and Urosurgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
²⁵ Institute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.
²⁶ Department of Internal Medicine. Hospital U M Valdecilla, University of Cantabria, IDIVAL, Santander, Spain.
²⁷ Stroke Research Centre, University College London, Institute of Neurology, London, UK.
²⁸ Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London, UK.
²⁹ Department of Neurosurgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
³⁰ Stroke Research Center, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
³¹ Institute for Human Genetics, University of Marburg, Marburg, Germany.
³² Department of Women's and Children's Health and Center for Molecular Medicine, Bioclinicum, Karolinska Institutet, Stockholm, Sweden.
³³ Department of Urology, Danderyds Hospital, Danderyd, Sweden.
³⁴ Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
³⁵ R&D Unit, Stockholms Sjukhem, Stockholm, Sweden.
³⁶ ME Gynecology and Reproduction Medicine, Karolinska University Hospital, and Dept of Clintec, Karolinska Institutet, Stockholm, Sweden.
³⁷ Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
³⁸ Department of Pediatric Surgery, Queen Silvia Children's Hospital, Gothenburg, Sweden.
³⁹ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
⁴⁰ Laboratory of Molecular Medicine and Cytogenetics, IRCCS Mondino Foundation, Pavia, Italy.
⁴¹ Pediatric Urology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁴² Paediatric Urology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
⁴³ Department for Pediatric Urology, Ordensklinikum Linz, Hospital of the Sisters of Charity, Linz, Austria.
⁴⁴ Division of Pediatric Urology, Department of Urology, University of Erlangen-Nürnberg, Erlangen, Germany.
⁴⁵ Department of Pediatric Surgery and Urology, Klinik Hallerwiese-Cnopfsche Kinderklinik, Nürnberg, Germany.
⁴⁶ Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
⁴⁷ Clinic for Paediatric Surgery and Paediatric Urology, Klinikum Bremen-Mitte, Bremen, Germany.
⁴⁸ Department of Pediatric Surgery and Urology, University Hospital Cologne, Cologne, Germany.
⁴⁹ Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany.
⁵⁰ Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
⁵¹ Department of Urology, Pediatric Urology Center, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
⁵² Department of Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
⁵³ Center of Pediatric Surgery Hannover, Hannover Medical School, Hannover, Germany.
⁵⁴ Department of Renal Medicine, University College London, London, UK.
⁵⁵ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
⁵⁶ Department of Child and Adolescent Psychiatry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁵⁷ Faculty of Health, School of Medicine, University of Witten/Herdecke, Witten, Germany.
⁵⁸ Institute for Neuroanatomy, University Hospital Bonn, University of Bonn, Bonn, Germany.
⁵⁹ Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
⁶⁰ Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany. Heiko.Reutter@uk-erlangen.de.
⁶¹ Division of Neonatology and Pediatric Intensive Care Medicine, Department of Pediatric and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. Heiko.Reutter@uk-erlangen.de.

^# Contributed equally.

PMID: 36352089
PMCID: PMC9646906
DOI: 10.1038/s42003-022-04092-3

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Enrico Mingardo et al. Commun Biol. 2022.

. 2022 Nov 9;5(1):1203.

doi: 10.1038/s42003-022-04092-3.

Authors

Affiliations

¹ Institute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany. enming@uni-bonn.de.
² Institute for Neuroanatomy, University Hospital Bonn, University of Bonn, Bonn, Germany. enming@uni-bonn.de.
³ Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany. enming@uni-bonn.de.
⁴ Centre for Genomic Medicine, University of Manchester, Manchester, UK.
⁵ Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.
⁶ Georg-Speyer-Haus, Frankfurt am Main, Germany.
⁷ Department of Women´s and Children´s Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.
⁹ Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, UK.
¹⁰ Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
¹¹ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
¹² Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany.
¹³ BRIDGE-Consortium Germany e.V., Mannheim, Germany.
¹⁴ Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany.
¹⁵ Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.
¹⁶ Institute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany.
¹⁷ Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center of Regensburg, Regensburg, Germany.
¹⁸ Department of Urology and Pediatric Urology, University Hospital of Ulm, Ulm, Germany.
¹⁹ Center for Pediatric, Adolescent and Reconstructive Urology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
²⁰ Department of Medical Sciences and Medical Genetics Unit, Città della Salute e della Scienza University Hospital, University of Torino, Torino, Italy.
²¹ Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy.
²² Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
²³ Department of Internal Medicine, Hospital U M Valdecilla, University of Cantabria, IDIVAL, Santander, Spain.
²⁴ Department of Urology and Urosurgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
²⁵ Institute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.
²⁶ Department of Internal Medicine. Hospital U M Valdecilla, University of Cantabria, IDIVAL, Santander, Spain.
²⁷ Stroke Research Centre, University College London, Institute of Neurology, London, UK.
²⁸ Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London, UK.
²⁹ Department of Neurosurgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
³⁰ Stroke Research Center, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
³¹ Institute for Human Genetics, University of Marburg, Marburg, Germany.
³² Department of Women's and Children's Health and Center for Molecular Medicine, Bioclinicum, Karolinska Institutet, Stockholm, Sweden.
³³ Department of Urology, Danderyds Hospital, Danderyd, Sweden.
³⁴ Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
³⁵ R&D Unit, Stockholms Sjukhem, Stockholm, Sweden.
³⁶ ME Gynecology and Reproduction Medicine, Karolinska University Hospital, and Dept of Clintec, Karolinska Institutet, Stockholm, Sweden.
³⁷ Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
³⁸ Department of Pediatric Surgery, Queen Silvia Children's Hospital, Gothenburg, Sweden.
³⁹ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
⁴⁰ Laboratory of Molecular Medicine and Cytogenetics, IRCCS Mondino Foundation, Pavia, Italy.
⁴¹ Pediatric Urology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁴² Paediatric Urology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
⁴³ Department for Pediatric Urology, Ordensklinikum Linz, Hospital of the Sisters of Charity, Linz, Austria.
⁴⁴ Division of Pediatric Urology, Department of Urology, University of Erlangen-Nürnberg, Erlangen, Germany.
⁴⁵ Department of Pediatric Surgery and Urology, Klinik Hallerwiese-Cnopfsche Kinderklinik, Nürnberg, Germany.
⁴⁶ Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
⁴⁷ Clinic for Paediatric Surgery and Paediatric Urology, Klinikum Bremen-Mitte, Bremen, Germany.
⁴⁸ Department of Pediatric Surgery and Urology, University Hospital Cologne, Cologne, Germany.
⁴⁹ Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany.
⁵⁰ Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
⁵¹ Department of Urology, Pediatric Urology Center, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
⁵² Department of Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
⁵³ Center of Pediatric Surgery Hannover, Hannover Medical School, Hannover, Germany.
⁵⁴ Department of Renal Medicine, University College London, London, UK.
⁵⁵ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
⁵⁶ Department of Child and Adolescent Psychiatry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁵⁷ Faculty of Health, School of Medicine, University of Witten/Herdecke, Witten, Germany.
⁵⁸ Institute for Neuroanatomy, University Hospital Bonn, University of Bonn, Bonn, Germany.
⁵⁹ Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
⁶⁰ Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany. Heiko.Reutter@uk-erlangen.de.
⁶¹ Division of Neonatology and Pediatric Intensive Care Medicine, Department of Pediatric and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. Heiko.Reutter@uk-erlangen.de.

^# Contributed equally.

PMID: 36352089
PMCID: PMC9646906
DOI: 10.1038/s42003-022-04092-3

Abstract

Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Chromosome regional association loci of CBE.**
The eight CBE regional association loci (red boxes in chromosomes) reside in chromosome 1, 3, 5, 11, 12, 17, and 20. In the panels, details of the genome-wide association loci: every dot represents an SNP (x axes) plotted to the relative –log₁₀(P value) (y axes). SNP are colored according to the relative r² value.

**Fig. 2. Expression heatmaps of genes that reside in the LD blocks of the eight significant genetic markers.**
a Genes expression pattern in mouse embryonic bladder from embryonic day E10.5 to E12.5, E12.5 to E15.5, and E10.5 to E15.5. b Genes expression pattern in human embryonic and fetal bladder from week 7 to 7–7.5, 7–7.5 to 7.5, 7 to 7.5, 7.5 to 8, 8 to 9, and 7 to 9. c Genes expression pattern of 3-year-old control bladder tissue compared to Bladder carcinoma (Bladder Ca), Bladder squamous cell carcinoma (Squamous cell Ca), Bladder transitional cell carcinoma (Transit. cell Ca), Ureter urothelial carcinoma (Ur. Urothelial Ca), Muscle invasive urothelial cancer (Mus. Inv. Urothelial Ca). Legend: Suppressed = gene is silenced and no expression is detected. Activated = gene shows expression after a silenced state.

See this image and copyright information in PMC

References

1. Ebert A-K, Reutter H, Ludwig M, Rösch WH. The exstrophy-epispadias complex. Orphanet J. Rare Dis. 2009;4:23. doi: 10.1186/1750-1172-4-23. - DOI - PMC - PubMed
1. Dahm P, Gschwend JE. Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur. Urol. 2003;44:672–681. doi: 10.1016/S0302-2838(03)00416-0. - DOI - PubMed
1. Williamson SR, Lopez-Beltran A, Montironi R, Cheng L. Glandular lesions of the urinary bladder: clinical significance and differential diagnosis. Histopathology. 2011;58:811–834. doi: 10.1111/j.1365-2559.2010.03651.x. - DOI - PubMed
1. Ebert AK, Zwink N, Reutter HM, Jenetzky E. A prevalence estimation of exstrophy and epispadias in Germany from Public Health Insurance Data. Front. Pediatr. 2021;9:648414. doi: 10.3389/fped.2021.648414. - DOI - PMC - PubMed
1. Reutter H, et al. 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. Hum. Mol. Genet. 2014;23:5536–5544. doi: 10.1093/hmg/ddu259. - DOI - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Affiliations

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Miscellaneous