Project Summary: Urinary urgency incontinence (UUI) is one of the most common conditions to impact women, and older women, in particular. When comparing women with and without urgency incontinence, those with UUI have lower quality of life scores and higher rates of anxiety and depression. While the incidence and prevalence of UUI has been well studied, the pathophysiology of the disease is poorly understood. In the majority of cases, UUI is classified as idiopathic or “age- related”. In these cases, there are likely numerous genetic, environmental, dietary, metabolic and clinical factors and inter-factor interactions that lead to the development of UUI and these interactions likely center around the disturbance of normal neural signaling which controls micturition. Improving our understanding of how UUI develops in women without an overt clinical condition and how the cholinergic signaling system is involved will likely contribute to an individualized treatment paradigm for managing UUI as well as the development of novel treatments. In this proposal we will use the robust longitudinal data present in the Nurses’ Health Study (NHS) and NHS II to classify the plasma levels of cholinergic metabolites in women with and without. We will investigate whether non-cholinergic metabolites and single nucleotide polymorphisms for UUI lead to this condition and how interactions between these variables and cholinergic metabolites and clinical and demographic risk factors lead to the development of UUI. We will also evaluate how dietary choline impacts the presence of cholinergic metabolites, and whether this interaction is associated with expression of the UUI phenotype.