Title:
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The genetic basis of urinary incontinence in women
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Background: Both urgency and stress urinary incontinence are heritable, with genetic factors contributing approximately half of total susceptibility. Aims: The overall aim of this project is to identify known and novel genetic polymorphisms associated with urgency and stress incontinence in women. Design: We systematically reviewed prior genetic association studies of incontinence, and other pelvic floor disorders. We then conducted a two stage GWAS, using women enrolled in NFBC1966, UK Twins, and ALSPAC for discovery, and women in six separate cohorts for replication. To prioritise likely susceptibility genes we measured gene expression in bladder biopsies, using whole genome microarrays, and PCR using custom microfluidic plates. Results: From prior studies of incontinence, and the related condition of prolapse among women, we conducted 13 meta-analyses for different polymorphisms, finding a single moderately credible association for a common variant in the ADRB3 gene associated with overactive bladder. From prior studies of lower urinary tract symptoms in men, we conducted 35 meta-analyses for different polymorphisms, finding a single moderately credible association for a common variant in the VDR gene associated with a composite of symptoms. For the GWAS discovery phase 8,997 women provided both incontinence phenotypes and genome wide genotypes. In meta-analysis, five loci included at least one genome-wide significant variant (p < 5x10⁻⁸). Twelve loci were taken forward for replication, with two demonstrating robust replication. In bladder biopsies we identified 1,115 significantly differentially expressed genes between stress and urgency incontinence. In the context of the previous literature, these results suggested EN1 and EDN1 as the most likely causal genes within the two replicated GWAS significant loci. Conclusions: This work highlights many of the challenges of identification of risk variants for complex conditions such as incontinence. The discovery of two novel risk loci for incontinence represents a significant advance in understanding the pathophysiology of these conditions.
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