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

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.

The effect of 8-OH-DPAT and dapoxetine on gene expression in the brain of male rats during ejaculation

“…For example in our study, the expression of Wnt3a is significantly elevated (fold change 7.53) at ejaculation (EJ group), and Wnt9b and Cdkn1a are up-regulated at ejaculation that is stimulated by 8-OH-DPAT and inhibited by dapoxetine treatment. The data reported by previous studies 40 have confirmed that Wnt3a suppresses cancer cell proliferation, and both Wnt9b and Cdkn1a suppress cancer progression41, 42, 43.…”

Combination of mouse models and genomewide association studies highlights novel genes associated with human kidney function

“…Some previous studies have linked GWAS results to evidence from mice. [43][44][45] By systematically linking well-powered GWAS summary results with corresponding phenotypes in thousands of mice and using additional databases to evaluate their expression during murine renal development, our approach is very comprehensive.…”

Role of the LF-SINE–Derived Distal ISL1 Enhancer in Patients with Classic Bladder Exstrophy

“…All patients were recruited in person by experienced physicians trained in the diagnosis of CBE and details of the recruitment process were outlined elsewhere. 14,24 Sequence Analysis Blood or saliva samples were obtained from patients and isolation of genomic DNA from blood was performed using a Chemagic Magnetic Separation Module I (Chemagen, Baesweiler, Germany). Genomic DNA from saliva samples was extracted by using the Oragene DNA Kit (DNA Genotek Inc., Kanata, Canada).…”