Genetic Contributions to Urgency Urinary Incontinence in Women

Abstract

Purpose To identify genetic variants associated with urgency urinary incontinence (UUI) in post-menopausal women. Materials and Methods A two-stage genome wide association analysis was conducted to identify variants associated with UUI. The Women’s Health Initiative-Genomics & Randomized Trials Network (GARNET) sub-study with 4,894 genotyped post-reproductive white women was randomly split into independent discovery and replication cohorts. Genome-wide imputation was performed using IMPUTE2 with the 1000-Genomes-ALL-Phase-I integrated variant set as a reference. Controls reported no UUI at enrollment or follow-up; cases reported monthly or greater UUI and leaked sufficiently to wet/soak underpants/clothes. Logistic regression models were used to predict UUI case versus control status based on genotype, assuming additive inheritance. Age, obesity, diabetes and depression were included in the models as covariates. Results Following quality control, 975,508 single nucleotide polymorphisms (SNPs) in 2,241 cases (discovery=1,102, replication=1,133) and 776 controls (discovery=405, replication=371) remained. Genotype imputation resulted in 9,077,347 SNPs and insertions/deletions with minor allele frequency >0.01 available for analysis. Meta-analysis of the discovery and replication samples identified six loci on chromosomes 5, 10, 11, 12 & 18 associated with UUI at p<10−6. Three of the loci were within genes, the zinc finger protein 521 (ZFP521) gene on chromosome 18q11, the ADAMTS16 gene on chromosome 5p15, and the CIT gene on chromosome 12q24. The other three loci were intergenic. Conclusions Although environmental factors also likely contribute, this first exploratory Genome-Wide Associated Study (GWAS) for UUI suggests that genetic variants in the ZFP521, CIT, and ADAMTS16 genes might account for some of the observed heritability of the condition.

Urinary incontinence in women

“…The discovery of new genetic risk variants for incontinence 172,173 and the interrogation of those variants as known causes of objectively measured bladder dysfunction might provide striking insight into the actual variation in human bladder physiology associated with incontinence. Accordingly, we might identify new subtypes of urgency incontinence at which we can direct targeted care.…”

Prevalence and risk factors of overactive bladder in Chinese children: A population‐based study

“…The mechanisms for the association between hereditary factors and OAB are complex and remain unexplained. Some genes, such as those encoding zinc finger proteins, ADAM metallopeptidase with thrombospondin type 1 motif 16 and threonine kinases, were found to contribute to LUTS …”

“…Some genes, such as those encoding zinc finger proteins, ADAM metallopeptidase with thrombospondin type 1 motif 16 and threonine kinases, were found to contribute to LUTS. 24 Several epidemiologic surveys have reported a prevalence of OAB of 9 to 16% in adults, which gradually increases with age. 25 In children, we found that the prevalence rates of overall, wet and dry OAB all decreased with age; age was a protective factor against OAB.…”

Urinary incontinence in women

“…Recent genome-wide association studies have attempted to shed light on the molecular pathogenesis of incontinence. The discovery of new genetic risk variants for incontinence 172,173 and the interrogation of those variants as known causes of objectively measured bladder dysfunction might provide striking insight into the actual variation in human bladder physiology associated with incontinence. Accordingly, we might identify new subtypes of urgency incontinence at which we can direct targeted care.…”