Genome-wide association studies (GWAS) have not identified replicable genetic risk loci for stress or urgency urinary incontinence.
We carried out a discovery stage case control GWAS in three independent discovery cohorts of European women (n=8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in six additional studies of European ancestry (n=4,069). We collected bladder biopsies from women with incontinence to further investigate bladder expression of implicated genes and pathways (n=50) and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models in METAL, and whole transcriptome analyses using Affymetrix arrays, with replication with TaqMan PCR.
In the discovery stage we identified 16 single nucleotide polymorphisms (SNPs) genotyped or imputed at five loci that reached genome-wide significance (p<5x10-8). In replication, rs138724718 on chromosome 2, near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the Endothelin 1 (EDN1) gene (replication p=0.0008) associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these two SNPs were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p<0.0001).
We uncovered two 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.
The Journal of urology. 2021 Apr 27 [Epub ahead of print]
Rufus Cartwright, Larissa Franklin, Kari A O Tikkinen, Ilkka Kalliala, Pawel Miotla, Tomasz Rechberger, Ifeoma Offiah, Steve McMahon, Barry O'Reilly, Sabrina Lince, Kirsten Kluivers, Wilke Post, Geert Poelmans, Melody R Palmer, Hunter Wessels, Andrew Wong, Diana Kuh, Mika Kivimaki, Meena Kumari, Massimo Mangino, Tim Spector, Jeremy A Guggenheim, Benjamin Lehne, N Maneka G De Silva, David M Evans, Debbie Lawlor, Ville Karhunen, Minna Mannikko, Malgorzata Marczak, Phillip R Bennett, Vik Khullar, Marjo-Riitta Järvelin, Andrew Walley
Department of Urogynaecology, Imperial College London, UK ., Women's Health Research Centre, Imperial College London, UK ., Department of Urology, University of Helsinki and Helsinki University Hospital, Finland., Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Finland., 2nd Department of Gynaecology, Medical University of Lublin, Poland., Peninsula Medical School, University of Plymouth, Plymouth, UK., Wolfson Institute, King's College London, UK., Department of Urogynaecology, University College Cork, Ireland., Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands., Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Department of Urology, University of Washington., MRC Unit for Lifelong Health and Ageing at UCL, UK., Department of Epidemiology and Public Health, University College London, UK ., Institute for Social & Economic Research, University of Essex, UK ., Department of Twin Research and Genetic Epidemiology, King's College London, London, UK., School of Optometry & Vision Sciences , Cardiff University, Cardiff, UK., Diamantina Institute, University of Queensland, Australia ., Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK ., Institute of Health Sciences, University of Oulu, Finland ., Department of Genetics and Microbiology, UMCS, Lublin, Poland., Institute for Reproductive and Developmental Biology (IRDB), Imperial College London, UK., Department of Epidemiology & Biostatistics, Imperial College London, UK.