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

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.

Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

“…While expression of Celsr3 in the developing CNS of mice was described previously [8][9][10] , we extended the expression profile of CELSR3/ Celsr3 to the embryonic and fetal bladder precursor tissues using human and mouse transcriptome data (GEO accession ID: GSE190641; Supplementary Fig. 1) 23 . These findings suggest a conserved role of CELSR3/Celsr3 not only during CNS but also during urinary tract development in vertebrates (Supplementary Fig.…”

“…All sequencing data are deposited in ClinVar (accession numbers: SCV004176841 -SCV004176856). Mouse RNA-seq data at stages E10.5, E12.5 and E15.5 were obtained from Gene Expression Omnibus (GEO accession ID: GSE190641) 23 . RNA-seq data of human embryonic and fetal bladder tissues were obtained from already deposited data at EMBL-EBI expression atlas (E-MTAB-6592).…”

The outcome and complications of modern staged repair surgery in newborns with classic bladder exstrophy in different genders: A retrospective study

“…The diagnosis of EEC was made either prenatally or immediately after birth through transabdominal ultrasonography and physical examination, respectively. Given the wide range of congenital anterior abdominal defect diseases, from epispadias to cloacal exstrophy, we only selected infants with classical manifestations of EEC, which includes pubic diastasis, an evaginated bladder, and usually a severe form of epispadias (Mingardo et al, 2022). All the patients were initially admitted to the neonatal intensive care unit.…”

EZH2 specifically regulatesISL1during embryonic urinary tract formation

“…We divided this region in three partially overlapping sequences that were cloned forward and flipped in pGL3-Basic plasmid for luciferase assays: (i) Fragment 1 ranged from 5.028 to 6.328 bp (1.300 bp) away from the ISL1 TSS, (ii) Fragment 2 from 5.871 to 7.150 bp away Manhattan plot of the CBE GWAS. The dotted box shows the region harboring ISL1 (Mingardo et al, 2022) and is zoomed into B) Overview of the genomic region where the luciferase is performed referred to the ISL1 gene. In detail, Fragment 1, Fragment 2 and Fragment 3 coordinates are shown relatively to the distance from the ISL1 transcription starting site (TSS) (top) and also in chromosome 5 coordinates (hg38 /lower).…”

“…The copyright holder for this preprint this version posted August 22, 2023. ; https://doi.org/10.1101/2023.08.21.554100 doi: bioRxiv preprint 3 genitals and in the severe cases spine and anus (Beaman et al, 2021). Our recent meta-analysis comprised seven independent discovery samples and identified eight genome-wide significant loci, seven of which were novel (Mingardo et al, 2022). The most significant marker (rs6874700) within the ISL1 region achieved a p value of 1.48 × 10 -24 .…”