The Genetic Basis of Urinary Incontinence in Women
Lead Research Organisation:
Imperial College London
Department Name: 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.
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.