Rufus Cartwright1,2, Larissa Franklin3, Kari A O Tikkinen4,5, Ilkka Kalliala6,7, Pawel Miotla8, Tomasz Rechberger8, Ifeoma Offiah9, Steve McMahon10, Barry O'Reilly11, Sabrina Lince12, Kirsten Kluivers12, Wilke M Post12, Geert Poelmans13, Melody R Palmer14, Hunter Wessells14, Andrew Wong15, Diana Kuh15, Mika Kivimaki16, Meena Kumari17, Massimo Mangino18,19, Tim Spector18,19, Jeremy A Guggenheim20, Benjamin Lehne2, N Maneka G De Silva2, David M Evans21,22, Debbie Lawlor22,23, Ville Karhunen, Minna Männikkö, Malgorzata Marczak24, Phillip R Bennett25,26, Vik Khullar1, Marjo-Riitta Järvelin2,27, Andrew Walley26. 1. Department of Urogynaecology, Imperial College London, UK . 2. Department of Epidemiology & Biostatistics, Imperial College London, UK. 3. Women's Health Research Centre, Imperial College London, UK. 4. Department of Urology, University of Helsinki and Helsinki University Hospital, Finland . 5. Department of Surgery, South Karelian Central Hospital, Lappeenranta, Finland. 6. Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Finland. 7. Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK. 8. 2nd Department of Gynaecology, Medical University of Lublin, Poland. 9. Peninsula Medical School, University of Plymouth, Plymouth, UK. 10. Wolfson Institute, King's College London, UK. 11. Department of Urogynaecology, University College Cork, Ireland. 12. Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 13. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 14. Department of Urology, University of Washington, Seattle, Washington. 15. MRC Unit for Lifelong Health and Ageing at UCL, UK. 16. Department of Epidemiology and Public Health, University College London, UK . 17. Institute for Social & Economic Research, University of Essex, UK . 18. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. 19. National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK. 20. School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK. 21. Diamantina Institute, University of Queensland, Australia . 22. Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK . 23. School of Social and Community Medicine, University of Bristol, UK. 24. Department of Genetics and Microbiology, UMCS, Lublin, Poland. 25. Institute for Reproductive and Developmental Biology (IRDB), Imperial College London, UK. 26. Institute of Medical & Biomedical Education and Genetics Research Centre, St George's University, London, UK. 27. Institute of Health Sciences, University of Oulu, Finland .
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: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) 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: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.
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: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) 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: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.