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).
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 children aged 5 to 20. 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.
Variants on chromosome 6 (rs12210989, 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 (rg = 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 body mass index (OR = 1.129 [95% CI: 1.081-1.178], P < .0001) polygenic risk.
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.
The Journal of urology. 2024 Aug 02 [Epub ahead of print]
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
Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark., deCODE genetics/Amgen, Reykjavík, Iceland., The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen and Aarhus, Denmark., NCRR - National Centre for Register-based Research, Aarhus University, Aarhus, Denmark., Faculty of Medicine, University of Iceland, Reykjavík, Iceland.