The Genetic Basis of Urinary Incontinence in Women

Lead Research Organisation: Imperial College London
Department Name: Dept of Surgery and Cancer

Abstract

Stress incontinence (leaking urine in association with exertion) and urge incontinence (leaking urine before being able to reach a toilet) are common distressing conditions that have a big impact on quality of life. We aim to discover why these conditions tend to run in families, and how the genes that cause these problems actually affect bladder function. We will test a large number of women for all the common sorts of genetic variation, and see whether these variants make it more likely for women to have symptoms of incontinence. We will then conduct more detailed genetic tests in patients with urge and stress incontinence, discovering how these variants change bladder function, and how they influence the expression of other genes in the bladder itself. The ultimate goals are to be able to predict who is at risk of developing incontinence, and to develop new strategies to prevent it happening, and new drugs to treat it more effectively.

Technical Summary

Aims:
To identify genetic polymorphisms associated with stress and urge incontinence in women, and understand how these influence bladder gene expression, and in vivo bladder function.

Objectives:
1. To conduct the first genome wide association study (GWAS) of stress and urge urinary incontinence in women, identifying loci associated with incontinence.
2. To fine map significant loci from the GWAS, identifying the susceptibility genes, and confirming the clinical relevance and in vivo functional effects of relevant SNPs and/or their associated genes.
3. To identify bladder specific expression quantitative trait loci (eQTL), relating significant SNPs to alterations in the bladder transcriptome using an integrative genomics approach.

Design:
Three main studies will correspond to these objectives:
1. GWAS of stress and urge incontinence using a two stage discovery and replication design, in the UK Twin Cohort, and Bristol ALSPAC Cohort.
2. Fine mapping study using patients with stress and urge incontinence as cases and controls. Women referred for clinical bladder function tests will be genotyped from saliva samples.
3. eQTL mapping using bladder biopsies taken at the time of cystoscopy in women with incontinence, who have been previously genotyped for significant SNPs.

Methodology:
1. The GWAS discovery set (UK Twin Cohort, n?8,000) will use existing phenotypes and genotypes (Illumina 660). The replication set (ALSPAC cohort, n?15,000), will use a new mailing of a validated self-completed questionnaire for incontinence phenotyping, as well as existing genotypes (Illumina 610). In both cohorts age, BMI, and parity will be considered as potential mediators.
2. For the fine mapping, loci with genome wide significance will be genotyped in detail (n?400) using a Sequenom MASSarray analyser, and associations measured with clinical diagnosis and quantitative urodynamic parameters, using chi square and multivariate mixed regression.
3. 5-10mg bladder biopsies will be collected and stored in RNAlater (n=34). Gene expression will be measured using Affymetrix Human Genome HgU133 Plus 2.0 microarrays, with validation using qPCR.

Scientific and medical opportunities:
Urinary incontinence is highly heritable, but no contributing genetic markers have been identified. Genome wide studies have revolutionised the search for the genetic causes of complex diseases. We expect that discovered SNPs will serve as markers of clinical risk for stress and urge incontinence, and through relation to gene expression, and bladder function, will help explain the underlying pathogenesis. The insights provided will potentially offer new drug targets, biomarkers, and preventative strategies.

Publications

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Albersen M (2014) Looking forward, looking back-10 years in urology. in Nature reviews. Urology

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Bhide A (2013) Erratum to: Biomarkers in overactive bladder in International Urogynecology Journal

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Bhide AA (2013) Biomarkers in overactive bladder. in International urogynecology journal

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Cartwright R (2015) Authors' reply. in BJOG : an international journal of obstetrics and gynaecology

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Cartwright R (2012) What was hot at the ICS meeting Glasgow, Scotland, 2011. in Neurourology and urodynamics

 
Description ALSPAC - University of Bristol 
Organisation University of Bristol
Department MRC Centre for Causal Analyses in Translational Epidemiology
Country United Kingdom 
Sector Public 
PI Contribution Shared work on the genetics of incontinence, using the ALSPAC resource.
Collaborator Contribution Provision of data, and collection of new phenotypes.
Impact Abstracts accepted for presentation at two international meetings.
Start Year 2012
 
Description NFBC66 
Organisation Finnish Birth Cohort
Country Finland 
Sector Academic/University 
PI Contribution New work on genetics of incontinence
Collaborator Contribution Collection of new phenotypes
Impact Not yet!
Start Year 2012
 
Description UK Twins 
Organisation King's College London
Department Department of Twin Research and Genetic Epidemiology
Country United Kingdom 
Sector Academic/University 
PI Contribution Shared work on genetics of incontinence and prolapse
Collaborator Contribution Collection of new phenotypes
Impact Presentation at International Continence Society Meeting 2013.
Start Year 2011