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

Mingardo E, Beaman G, Grote P, Nordenskjöld A, Newman W, Woolf AS, Eckstein M, Hilger AC, Dworschak GC, Rösch W, Ebert AK, Stein R, Brusco A, Di Grazia M, Tamer A, Torres FM, Hernandez JL, Erben P, Maj C, Olmos JM, Riancho JA, Valero C, Hostettler IC, Houlden H, Werring DJ, Schumacher J, Gehlen J, Giel AS, Buerfent BC, Arkani S, Åkesson E, Rotstein E, Ludwig M, Holmdahl G, Giorgio E, Berettini A, Keene D, Cervellione RM, Younsi N, Ortlieb M, Oswald J, Haid B, Promm M, Neissner C, Hirsch K, Stehr M, Schäfer FM, Schmiedeke E, Boemers TM, van Rooij IA, Feitz WF, Marcelis CL, Lacher M, Nelson J, Ure B, Fortmann C, Gale DP, Chan MM, Ludwig KU, Nöthen MM, Heilmann S, Zwink N, Jenetzky E, Odermatt B, Knapp M, Reutter H (2022)

Publication Type: Journal article

Publication year: 2022


Book Volume: 5

Article Number: 1203

Journal Issue: 1

DOI: 10.1038/s42003-022-04092-3


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.

Authors with CRIS profile

Involved external institutions

University of Manchester GB United Kingdom (GB) Philipps-Universität Marburg DE Germany (DE) Karolinska Institute SE Sweden (SE) Karolinska University Hospital / Karolinska Universitetssjukhuset SE Sweden (SE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Ordensklinikum Linz GmbH Barmherzige Schwestern AT Austria (AT) Universitätsklinikum Köln DE Germany (DE) Universität Leipzig DE Germany (DE) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Universitätsklinikum Bonn DE Germany (DE) Goethe-Universität Frankfurt am Main DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE) Universitätsklinikum Ulm DE Germany (DE) Universitätsklinikum Mannheim DE Germany (DE) Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino IT Italy (IT) I.R.C.C.S. materno infantile Burlo Garofolo IT Italy (IT) Complejo Hospitalario Universitario de Santiago de Compostela ES Spain (ES) Universidad de Cantabria (UC) ES Spain (ES) BRIDGE Consortium e.V. (Bladder Cancer Research Initiative for Drug Targets Germany) DE Germany (DE) University College London (UCL) GB United Kingdom (GB) National Hospital For Neurology and Neurosurgery GB United Kingdom (GB) Drottning Silvias barnsjukhus SE Sweden (SE) Università degli Studi di Pavia IT Italy (IT) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico IT Italy (IT) Royal Manchester Children's Hospital GB United Kingdom (GB) Cnopf'sche Kinderklinik DE Germany (DE) Klinikverbund Bremen (Gesundheit Nord) DE Germany (DE) Universitätsmedizin der Johannes Gutenberg-Universität Mainz DE Germany (DE)

How to cite


Mingardo, E., Beaman, G., Grote, P., Nordenskjöld, A., Newman, W., Woolf, A.S.,... Reutter, H. (2022). A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy. Communications Biology, 5(1). https://doi.org/10.1038/s42003-022-04092-3


Mingardo, Enrico, et al. "A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy." Communications Biology 5.1 (2022).

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