Exploring the Genetic Risk of Childhood Daytime Urinary Incontinence: A Genome-Wide Association Study

Anders Breinbjerg; Cecilie Siggaard Jørgensen; G Bragi Walters; Jakob Grove; Thomas D Als; Konstantinos Kamperis; Lilja Stéfansdóttir; Janne P Thirstrup; Britt Borg; Clara Albiñana; Bjarni J Vilhjálmsson; Viðar Ö Eðvarðsson; Hreinn Stefánsson; Preben B Mortensen; Esben Agerbo; Thomas Werge; Anders Børglum; Ditte Demontis; Kári Stefánsson; Søren Rittig; Jane Hvarregaard Christensen

doi:10.1097/JU.0000000000004187

Exploring the Genetic Risk of Childhood Daytime Urinary Incontinence: A Genome-Wide Association Study

J Urol. 2024 Dec;212(6):851-861. doi: 10.1097/JU.0000000000004187. Epub 2024 Aug 2.

Authors

Anders Breinbjerg^{1

2}, Cecilie Siggaard Jørgensen^{1

2}, G Bragi Walters^{3

4}, Jakob Grove^{5

6

7

8

9}, Thomas D Als^{5

6

7

8}, Konstantinos Kamperis^{1

2}, Lilja Stéfansdóttir³, Janne P Thirstrup^{5

6

8}, Britt Borg^{1

2}, Clara Albiñana¹⁰, Bjarni J Vilhjálmsson^{5

9

10

11}, Viðar Ö Eðvarðsson^{4

12}, Hreinn Stefánsson³, Preben B Mortensen^{5

10

13}, Esben Agerbo^{5

10

13}, Thomas Werge^{5

14

15}, Anders Børglum^{5

6

7

8}, Ditte Demontis^{5

6

8

11}, Kári Stefánsson^{3

4}, Søren Rittig^{1

2}, Jane Hvarregaard Christensen^{5

6

7

8}

Affiliations

¹ Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
² Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
³ deCODE genetics/Amgen, Reykjavík, Iceland.
⁴ Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
⁵ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen and Aarhus, Denmark.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷ Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
⁸ Centre for Genomics and Personalized Medicine, CGPM, Aarhus University, Aarhus, Denmark.
⁹ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
¹⁰ NCRR - National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
¹¹ Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
¹² Children's Medical Center, Landspitali-The National University Hospital of Iceland, Reykjavík, Iceland.
¹³ CIRRAU-Center for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
¹⁴ Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

PMID: 39093873
DOI: 10.1097/JU.0000000000004187

Abstract

Purpose: Childhood incontinence is stigmatized and underprioritized, and a basic understanding of its pathogenesis is missing. Our goal was to identify risk-conferring genetic variants in daytime urinary incontinence (DUI).

Materials and methods: We conducted a genome-wide association study in the Danish iPSYCH2015 cohort. Cases (3024) were identified through DUI diagnosis codes and redeemed prescriptions for DUI medication in individuals aged 5 to 20 years. Controls (30,240), selected from the same sample, were matched to cases on sex and psychiatric diagnoses, if any, and down-sampled to a 1:10 case:control ratio. Replication was performed in the Icelandic deCODE cohort (5475 cases/287,773 controls). Single-nucleotide polymorphism heritability was calculated using the genome-based restricted maximum likelihood method. Cross-trait genetic correlation was estimated using linkage disequilibrium score regression. Polygenic risk scores generated with LDpred2-auto and BOLT-LMM were assessed for association.

Results: Variants on chromosome 6 (rs12210989, odds ratio [OR] 1.24, 95% CI 1.17-1.32, P = 3.21 × 10^-12) and 20 (rs4809801, OR 1.18, 95% CI 1.11-1.25, P = 3.66 × 10^-8) reached genome-wide significance and implicated the PRDM13 and RIPOR3 genes. Chromosome 6 findings were replicated (P = .024, OR 1.09, 95% CI 1.01-1.16). Liability scale heritability ranged from 10.20% (95% CI 6.40%-14.00%) to 15.30% (95% CI 9.66%-20.94%). DUI and nocturnal enuresis showed positive genetic correlation (r_g = 1.28 ± 0.38, P = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR 1.098, 95% CI 1.046-1.152, P < .0001) and BMI (OR 1.129, 95% CI 1.081-1.178, P < .0001) polygenic risk.

Conclusions: Common genetic variants contribute to the risk of childhood DUI, and genes important in neuronal development and detrusor smooth muscle activity were implicated. These findings may help guide identification of new treatment targets.

Keywords: child; diurnal enuresis; genetic loci; genome-wide association study; urinary incontinence.

MeSH terms

Adolescent
Case-Control Studies
Child
Child, Preschool
Denmark / epidemiology
Diurnal Enuresis / epidemiology
Diurnal Enuresis / genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Male
Polymorphism, Single Nucleotide*
Risk Factors
Young Adult