Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence

No AccessJournal of UrologyAdult Urology1 Sep 2021Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary IncontinenceThis article is commented on by the following:Editorial Comment 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 M. Post, Geert Poelmans, Melody R. Palmer, Hunter Wessells, 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 Männikkö, Malgorzata Marczak, Phillip R. Bennett, Vik Khullar, Marjo-Riitta Järvelin, and Andrew Walley Rufus CartwrightRufus Cartwright *Correspondence: Department of Epidemiology & Biostatistics, Imperial College London, Norfolk Place, London, WG 1PG United Kingdom ( E-mail Address: [email protected] Department of Urogynaecology, Imperial College London, UK Department of Epidemiology & Biostatistics, Imperial College London, UK , Larissa FranklinLarissa Franklin Women's Health Research Centre, Imperial College London, UK , Kari A. O. TikkinenKari A. O. Tikkinen Department of Urology, University of Helsinki and Helsinki University Hospital, Finland ; Department of Surgery, South Karelian Central Hospital, Lappeenranta, Finland; , Ilkka KallialaIlkka Kalliala Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Finland; Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK , Pawel MiotlaPawel Miotla 2nd Department of Gynaecology, Medical University of Lublin, Poland; , Tomasz RechbergerTomasz Rechberger 2nd Department of Gynaecology, Medical University of Lublin, Poland; , Ifeoma OffiahIfeoma Offiah Peninsula Medical School, University of Plymouth, Plymouth, UK , Steve McMahonSteve McMahon Wolfson Institute, King's College London, UK , Barry O'ReillyBarry O'Reilly Department of Urogynaecology, University College Cork, Ireland; , Sabrina LinceSabrina Lince Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands , Kirsten KluiversKirsten Kluivers Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands , Wilke M. PostWilke M. Post Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands , Geert PoelmansGeert Poelmans Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands , Melody R. PalmerMelody R. Palmer Department of Urology, University of Washington, Seattle, Washington , Hunter WessellsHunter Wessells Department of Urology, University of Washington, Seattle, Washington , Andrew WongAndrew Wong MRC Unit for Lifelong Health and Ageing at UCL, UK , Diana KuhDiana Kuh MRC Unit for Lifelong Health and Ageing at UCL, UK , Mika KivimakiMika Kivimaki Department of Epidemiology and Public Health, University College London, UK , Meena KumariMeena Kumari Institute for Social & Economic Research, University of Essex, UK , Massimo ManginoMassimo Mangino Department of Twin Research and Genetic Epidemiology, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK , Tim SpectorTim Spector Department of Twin Research and Genetic Epidemiology, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK , Jeremy A. GuggenheimJeremy A. Guggenheim School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK , Benjamin LehneBenjamin Lehne Department of Epidemiology & Biostatistics, Imperial College London, UK , N. Maneka G. De SilvaN. Maneka G. De Silva Department of Epidemiology & Biostatistics, Imperial College London, UK , David M. EvansDavid M. Evans Diamantina Institute, University of Queensland, Australia Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK , Debbie LawlorDebbie Lawlor Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK School of Social and Community Medicine, University of Bristol, UK , Ville KarhunenVille Karhunen , Minna MännikköMinna Männikkö , Malgorzata MarczakMalgorzata Marczak Department of Genetics and Microbiology, UMCS, Lublin, Poland; , Phillip R. BennettPhillip R. Bennett Institute for Reproductive and Developmental Biology (IRDB), Imperial College London, UK Institute of Medical & Biomedical Education and Genetics Research Centre, St George's University, London, UK , Vik KhullarVik Khullar Department of Urogynaecology, Imperial College London, UK , Marjo-Riitta JärvelinMarjo-Riitta Järvelin Department of Epidemiology & Biostatistics, Imperial College London, UK Institute of Health Sciences, University of Oulu, Finland ; , and Andrew WalleyAndrew Walley Institute of Medical & Biomedical Education and Genetics Research Centre, St George's University, London, UK on behalf of the IGNITE Consortium View All Author Informationhttps://doi.org/10.1097/JU.0000000000001822AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail 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. 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Tikkinen was supported by the Academy of Finland (276046, 309387), Competitive Research Funding of the Helsinki and Uusimaa Hospital District (TYH2019321), Jane and Aatos Erkko Foundation, and Sigrid Jusélius Foundation. Pawel Miotla, Tomasz Rechberger, and Malgorzata Marczak were supported by National Science Centre, Poland (2011/01/D/NZ7/04708). The NSHD is funded by the UK Medical Research Council. Diana Kuh and Andrew Wong are supported by the UK Medical Research Council (MC_UU_00019/1). Debbie A. Lawlor is supported by the UK Medical Research Council (MC_UU_0001/5), Joint UK Research Councils (G1001357), Wellcome Trust (WT092830M and WT088806), and UK National Institute of Medical Research (NF-SI-0166-10196). David Evans is supported by the UK Medical Research Council (MC_UU_1201/4). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2), and the University of Bristol provide core support for ALSPAC. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust and King's College London. SNP Genotyping for Twins UK was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The DCCT/EDIC project is supported by contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, National Eye Institute, National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program and the Clinical and Translational Science Awards Program, National Center for Research Resources, and by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. Mika Kivimäki is supported by the Medical Research Council (MR/R024227/1), the National Institute on Aging (R01AG056477), and the Wellcome Trust (221854/Z/20/Z). NFBC1966 received financial support from University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, ERDF European Regional Development Fund Grant no. 539/2010 A31592. Marjo-Riitta Järvelin and the NFBC1966 team are funded by Academy of Finland (285547), University Hospital Oulu, Finland (75617), NHLBI through the STAMPEED program (5R01HL087679-02, 1RL1MH083268-01) and ERDF European Regional Development Fund (539/2010 A31592). The NFBC1966 is also funded by EU-H2020 EDCMET (825762), EU-H2020 EUCAN Connect (824989), EU H2020-MSCA-ITN-2016 CAPICE Marie Sklodowska-Curie grant (721567) and the Medical Research Council, UK (MRC/BBSRC MR/S03658X/1 (JPI HDHL)). Melody Palmer and Hunter Wessells were supported by 5T32DK55017 and 5R01DK83927. Contributorship Statement: Planned the study: Cartwright, Tikkinen, Khullar, Järvelin, Bennett, Walley. Analyses: Cartwright, Miotla, Kalliala, Offiah, Palmer, Post, Poelmans, Wong, Mangino, Guggenheim, Lehne, De Silva, Evans, Karhunen. Sample collection, study administration and sample preparation: Cartwright, Franklin, Miotla, Rechberger, Marczak, Lince, Kluivers, Kumari, Mannikko, Karhunen, Khullar, O'Reilly. Supervision: Tikkinen, O'Reilly, McMahon, Kluivers, Wessels, Kuh, Kivimaki, Kumari, Spector, Lawlor, Bennett, Khullar, Järvelin, Walley. © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of UrologyJun 16, 2021, 12:00:00 AMEditorial Comment Volume 206Issue 3September 2021Page: 679-687Supplementary Materials Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.Keywordsgenome-wide association studyurinary incontinence, urgegeneticsgenomicsurinary incontinence, stressMetricsAuthor Information Rufus Cartwright Department of Urogynaecology, Imperial College London, UK Department of Epidemiology & Biostatistics, Imperial College London, UK *Correspondence: Department of Epidemiology & Biostatistics, Imperial College London, Norfolk Place, London, WG 1PG United Kingdom ( E-mail Address: [email protected] More articles by this author Larissa Franklin Women's Health Research Centre, Imperial College London, UK More articles by this author Kari A. O. Tikkinen Department of Urology, University of Helsinki and Helsinki University Hospital, Finland ; Department of Surgery, South Karelian Central Hospital, Lappeenranta, Finland; More articles by this author Ilkka Kalliala Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Finland; Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK More articles by this author Pawel Miotla 2nd Department of Gynaecology, Medical University of Lublin, Poland; More articles by this author Tomasz Rechberger 2nd Department of Gynaecology, Medical University of Lublin, Poland; More articles by this author Ifeoma Offiah Peninsula Medical School, University of Plymouth, Plymouth, UK More articles by this author Steve McMahon Wolfson Institute, King's College London, UK More articles by this author Barry O'Reilly Department of Urogynaecology, University College Cork, Ireland; More articles by this author Sabrina Lince Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands More articles by this author Kirsten Kluivers Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands More articles by this author Wilke M. Post Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands More articles by this author Geert Poelmans Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands More articles by this author Melody R. Palmer Department of Urology, University of Washington, Seattle, Washington More articles by this author Hunter Wessells Department of Urology, University of Washington, Seattle, Washington More articles by this author Andrew Wong MRC Unit for Lifelong Health and Ageing at UCL, UK More articles by this author Diana Kuh MRC Unit for Lifelong Health and Ageing at UCL, UK More articles by this author Mika Kivimaki Department of Epidemiology and Public Health, University College London, UK More articles by this author Meena Kumari Institute for Social & Economic Research, University of Essex, UK More articles by this author Massimo Mangino Department of Twin Research and Genetic Epidemiology, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK More articles by this author Tim Spector Department of Twin Research and Genetic Epidemiology, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK More articles by this author Jeremy A. Guggenheim School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK More articles by this author Benjamin Lehne Department of Epidemiology & Biostatistics, Imperial College London, UK More articles by this author N. Maneka G. De Silva Department of Epidemiology & Biostatistics, Imperial College London, UK More articles by this author David M. Evans Diamantina Institute, University of Queensland, Australia Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK More articles by this author Debbie Lawlor Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK School of Social and Community Medicine, University of Bristol, UK More articles by this author Ville Karhunen More articles by this author Minna Männikkö More articles by this author Malgorzata Marczak Department of Genetics and Microbiology, UMCS, Lublin, Poland; More articles by this author Phillip R. Bennett Institute for Reproductive and Developmental Biology (IRDB), Imperial College London, UK Institute of Medical & Biomedical Education and Genetics Research Centre, St George's University, London, UK More articles by this author Vik Khullar Department of Urogynaecology, Imperial College London, UK More articles by this author Marjo-Riitta Järvelin Department of Epidemiology & Biostatistics, Imperial College London, UK Institute of Health Sciences, University of Oulu, Finland ; More articles by this author Andrew Walley Institute of Medical & Biomedical Education and Genetics Research Centre, St George's University, London, UK More articles by this author Expand All Funding: IUGA Basic Science Grant, ICS Emerging Team Grant. Rufus Cartwright was funded by a UK Medical Research Council Research Training Fellowship. Kari A.O. Tikkinen was supported by the Academy of Finland (276046, 309387), Competitive Research Funding of the Helsinki and Uusimaa Hospital District (TYH2019321), Jane and Aatos Erkko Foundation, and Sigrid Jusélius Foundation. Pawel Miotla, Tomasz Rechberger, and Malgorzata Marczak were supported by National Science Centre, Poland (2011/01/D/NZ7/04708). The NSHD is funded by the UK Medical Research Council. Diana Kuh and Andrew Wong are supported by the UK Medical Research Council (MC_UU_00019/1). Debbie A. Lawlor is supported by the UK Medical Research Council (MC_UU_0001/5), Joint UK Research Councils (G1001357), Wellcome Trust (WT092830M and WT088806), and UK National Institute of Medical Research (NF-SI-0166-10196). David Evans is supported by the UK Medical Research Council (MC_UU_1201/4). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2), and the University of Bristol provide core support for ALSPAC. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust and King's College London. SNP Genotyping for Twins UK was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The DCCT/EDIC project is supported by contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, National Eye Institute, National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program and the Clinical and Translational Science Awards Program, National Center for Research Resources, and by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. Mika Kivimäki is supported by the Medical Research Council (MR/R024227/1), the National Institute on Aging (R01AG056477), and the Wellcome Trust (221854/Z/20/Z). NFBC1966 received financial support from University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, ERDF European Regional Development Fund Grant no. 539/2010 A31592. Marjo-Riitta Järvelin and the NFBC1966 team are funded by Academy of Finland (285547), University Hospital Oulu, Finland (75617), NHLBI through the STAMPEED program (5R01HL087679-02, 1RL1MH083268-01) and ERDF European Regional Development Fund (539/2010 A31592). The NFBC1966 is also funded by EU-H2020 EDCMET (825762), EU-H2020 EUCAN Connect (824989), EU H2020-MSCA-ITN-2016 CAPICE Marie Sklodowska-Curie grant (721567) and the Medical Research Council, UK (MRC/BBSRC MR/S03658X/1 (JPI HDHL)). Melody Palmer and Hunter Wessells were supported by 5T32DK55017 and 5R01DK83927. Contributorship Statement: Planned the study: Cartwright, Tikkinen, Khullar, Järvelin, Bennett, Walley. Analyses: Cartwright, Miotla, Kalliala, Offiah, Palmer, Post, Poelmans, Wong, Mangino, Guggenheim, Lehne, De Silva, Evans, Karhunen. Sample collection, study administration and sample preparation: Cartwright, Franklin, Miotla, Rechberger, Marczak, Lince, Kluivers, Kumari, Mannikko, Karhunen, Khullar, O'Reilly. Supervision: Tikkinen, O'Reilly, McMahon, Kluivers, Wessels, Kuh, Kivimaki, Kumari, Spector, Lawlor, Bennett, Khullar, Järvelin, Walley. Advertisement PDF DownloadLoading ...