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No AccessJournal of UrologyAdult Urology1 Sep 2021

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

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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.

References

  • 1. : Structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. Am J Obstet Gynecol 1994; 170: 1713. Crossref, MedlineGoogle Scholar
  • 2. : A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature. Eur Urol 2009; 56: 810. Crossref, MedlineGoogle Scholar
  • 3. : Incontinence: preoperative urodynamics—self evident or evidently unnecessary?Nat Rev Urol 2015; 12: 539. Crossref, MedlineGoogle Scholar
  • 4. : On irritability of the bladder. Lancet 1854; 63: 637. CrossrefGoogle Scholar
  • 5. : Genetics and the lower urinary tract. Neurourol Urodyn 2010; 29: 609. Crossref, MedlineGoogle Scholar
  • 6. : Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women. Am J Obstet Gynecol 2015; 212: 199. CrossrefGoogle Scholar
  • 7. : Genetic contributions to urgency urinary incontinence in women. J Urol 2015; 193: 2020. LinkGoogle Scholar
  • 8. : Uncovering loci associated with urinary incontinence in African and Hispanic American women. American Society for Human Genetics, Annual Meeting 2013, abstract 914F p152. Available at https://www.ashg.org/wp-content/uploads/2019/10/2013-poster-abstracts.pdf. Google Scholar
  • 9. : Genome-wide association study for urinary and fecal incontinence in women. J Urol 2020; 203: 978. LinkGoogle Scholar
  • 10. : In vitro and in vivo relaxation of urinary bladder smooth muscle by the selective myosin II inhibitor, blebbistatin. BJU Int 2011; 107: 310. Crossref, MedlineGoogle Scholar
  • 11. : Differential roles of peripheral and spinal endothelin receptors in the micturition reflex in rats. J Urol 2004; 172: 1533. LinkGoogle Scholar
  • 12. : Emerging pharmacological targets in overactive bladder therapy: experimental and clinical evidences. Int Urogynecol J 2008; 19: 583. CrossrefGoogle Scholar
  • 13. : Future direction in pharmacotherapy for non-neurogenic male lower urinary tract symptoms. Eur Urol 2013; 64: 610. Crossref, MedlineGoogle Scholar
  • 14. : Genetic variation in the scavenger receptor MARCO and its association with chronic obstructive pulmonary disease and lung infection in 10,604 individuals. Respiration 2013; 85: 144. Crossref, MedlineGoogle Scholar
  • 15. : Murine bladder imaging by 2-photon microscopy: an experimental study of morphology. J Urol 2014; 192: 973. LinkGoogle Scholar
  • 16. : The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio 2014; 5: e01283. Crossref, MedlineGoogle Scholar
  • 17. : Overactive bladder in women: does low-count bacteriuria matter? A review. Neurourol Urodyn 2011; 30: 32. Crossref, MedlineGoogle Scholar
  • 18. : Associations between individual lower urinary tract symptoms and bacteriuria in random urine samples in women. Neurourol Urodyn 2015; 34: 429. Crossref, MedlineGoogle Scholar

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.

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