Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence
Rufus Cartwright, Larissa Franklin, Kari A.O. Tikkinen, Ilkka Kalliala, Paweł Miotła, Tomasz Rechberger, Ifeoma Offiah, Steve McMahon, Barry O’Reilly, Sabrina L. Lince, Kirsten B. Kluivers, Wilke M. Post, Geert Poelmans, Melody R. Palmer, Hunter Wessells, Andrew Wong, Diana Kuh, Mika Kivimäki, Meena Kumari, Massimo Mangino, Tim D. Spector, Jeremy A. Guggenheim, Benjamin Lehne, N. Maneka G. De Silva, David M. Evans, Debbie A. Lawlor, Ville Karhunen, Minna Männikkö, Małgorzata Marczak, Phillip R. Bennett, Vik Khullar, Marjo‐Riitta Järvelin, Andrew J. Walley
Abstract
PURPOSE: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence. MATERIALS AND METHODS: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction. RESULTS: ) gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001). CONCLUSIONS: ), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.