Bennett, P

Cartwright, R

Consortium, IGNITE

Jarvelin, M

Khullar, V

Miotla, P

Walley, A

St George's Online Research Archive

  Print this Page for Your Records Close WindowControl/Tracking Number: 2017-A-2552-ESHGActivity: ESHG AbstractCurrent Date/Time: 2/13/2017 3:30:23 PMGenome wide association study identifies two novel loci associated with female stress and urgency urinaryincontinence Author Block: R. Cartwright1, M. Jarvelin1, P. Miotla2, V. Khullar1, P. Bennett1, A. Walley3, the IGNITE Consortium; 1Imperial College London, London, United Kingdom, 2University of Lublin, Lublin, Poland, 3St George's MedicalSchool, London, United Kingdom. Abstract:Introduction: Stress and urgency incontinence are heritable, but no risk loci have been identified. We undertooka GWAS, using three European cohorts, followed by replication in six further studies, with supplementarytranscriptomic analyses using human bladder biopsies.Materials and Methods: Genotyping in discovery cohorts (n=8,979) was conducted using Illumina arrays.Replication genotyping used competitive PCR (n=4,069). Biopsies from women with urgency or stressincontinence were run on Affymetrix-U133 arrays.Results: Discovery analyses identified five genome-wide significant loci. Two loci replicated: rs138724718(p=3.39x10-09) and rs34998271 (p=1.70x10-09). In analysis of differential expression, the top-ranked process(GO:0003012, p=7.5x10-10), includes CHRM3 (fold difference:4.23, p=0.0007), which is the main drug target forurgency incontinence, SULF2 (fold difference:1.52, p=0.005) in the top locus from the discovery phase, and EDN1(fold difference:-1.60, p=0.09) in the top locus from the replication phase.Conclusions: We identified two genetic variants strongly associated with urinary incontinence. The first,rs138724718, is situated near MARCO, with a role in host defense. The second, rs34998271, is situated near EDN1a potent constrictor of smooth muscle, which was differentially expressed in bladder. This work highlights themyogenic and urotheliogenic mechanisms for incontinence, and suggests the potential of endothelin modulatingdrugs for urgency incontinence.Chr GRCh37Position SNPEffectAlleleOtherAllele MAF PhenotypeDiscovery Cohorts(n=8,997)Replication Cohorts(n=4,069) OverallOR 95%CI p OR 95%CI p p20 46424160 rs139329202 c g 0.01 UUI 8.50 4.12-17.55 8.07x10-9 1.35 0.82-2.21 0.238 2.38x10-056 1430664 rs146033157 a t 0.03 UUI 0.33 0.23-0.48 1.73x10-8 0.97 0.35-2.71 0.960 n/a14 55489229 rs146757102 a g 0.05 UUI 0.45 0.34-0.60 1.95x10-8 1.13 0.87-1.45 0.360 5.12x10-037 141328145 rs78851245 t c 0.02 Any UI 3.22 2.13-4.86 2.92x10-8 1.46 1.00-21.3 0.051 2.11x10-077 34354797 rs78878767 a c 0.01 UUI 4.26 2.56-7.10 3.04x10-8 0.86 0.51-1.43 0.556 2.11x10-073 55473083 rs13059018 c g 0.07 SUI 0.70 0.61-0.81 1.01x10-7 1.14 1.00-1.29 0.054 1.40x10-0612 11049362 rs201363123 ag a 0.06 Any UI 0.65 0.56-0.76 1.03x10-7 1.14 1.00-1.29 0.053 5.43x10-051 154881110 rs1218596 t c 0.06 Any UI 0.64 0.55-0.75 1.04x10-7 0.95 0.75-1.20 0.681 4.49x10-0611 39642765 rs10768519 a c 0.26 UUI 0.80 0.74-0.87 2.26x10-7 1.00 0.85-1.17 0.954 1.40x10-049 105517298 rs72738866 t c 0.26 SUI 0.79 0.71-0.87 2.55x10-7 1.01 0.89-1.14 0.895 5.97x10-052 119587824 rs138724718 a g 0.02 SUI 1.85 1.47-2.35 2.89x10-7 1.73 1.20-2.48 0.003 3.39x10-096 12533066 rs34998271 a g 0.05 UUI 1.70 1.40-2.074.97 x10-7 1.551.20-2.01 0.0008 1.70x10-09ESHG Conference c/o Vienna Medical AcademyAlser Strasse 4, A-1090 Vienna, AustriaTel: (+43/1) 405 13 83-22Fax (+43/1) 407 82 74Leave OASIS Feedback Leave OASIS FeedbackPowered by cOASIS, The Online Abstract Submission and Invitation System SM© 1996 - 2017 CTI Meeting Technology All rights reserved.:Author Disclosure Information: R. Cartwright: None. M. Jarvelin: None. P. Miotla: None. V. Khullar: None. P. Bennett: None. A. Walley: None. Topic (Complete):  03. Internal organs & endocrinology (lung, kidney, liver, gastrointestinal) Keyword (Complete):  Incontinence Presentation Preference (Complete):  Oral preferred Awards - Fellowships (Complete):      I apply for the Young Investigator Award: Yes     I am a: Post-doc researcher     Date of PhD/MD - dd.mm.yyyy: : 01.04.2016     Application for Fellowship: No     Application for Fellowship: No     Application for Fellowship: Yes     Status: Complete

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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