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

Rufus Cartwright^{1

2}, Larissa Franklin³, Kari A O Tikkinen^{4

5}, Ilkka Kalliala^{6

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 Mangino^{18

19}, Tim Spector^{18

19}, Jeremy A Guggenheim²⁰, Benjamin Lehne², N Maneka G De Silva², David M Evans^{21

22}, Debbie Lawlor^{22

23}, Ville Karhunen, Minna Männikkö, Malgorzata Marczak²⁴, Phillip R Bennett^{25

26}, Vik Khullar¹, Marjo-Riitta Järvelin^{2

27}, Andrew Walley²⁶

Affiliations

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 .

PMID: 33904754
DOI: 10.1097/JU.0000000000001822

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

Rufus Cartwright et al. J Urol. 2021 Sep.

. 2021 Sep;206(3):679-687.

doi: 10.1097/JU.0000000000001822. Epub 2021 Apr 27.

Authors

Affiliations

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 .

PMID: 33904754
DOI: 10.1097/JU.0000000000001822

Erratum in

Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence.
[No authors listed] [No authors listed] J Urol. 2023 Sep;210(3):569. doi: 10.1097/JU.0000000000003604. Epub 2023 Sep 1. J Urol. 2023. PMID: 37555609 No abstract available.

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.

Keywords: genetics; genome-wide association study; genomics; urinary incontinence, stress; urinary incontinence, urge.

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Editorial Comment.
Carnes MU, Richter HE. Carnes MU, et al. J Urol. 2021 Sep;206(3):687. doi: 10.1097/JU.0000000000001822.01. Epub 2021 Jun 16. J Urol. 2021. PMID: 34130486 No abstract available.

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

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

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