Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
J Urol. 2024 Dec;212(6):851-861. doi: 10.1097/JU.0000000000004187. Epub 2024 Aug 2.
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 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.
Variants on chromosome 6 (rs12210989, odds ratio [OR] 1.24, 95% CI 1.17-1.32, = 3.21 × 10) and 20 (rs4809801, OR 1.18, 95% CI 1.11-1.25, = 3.66 × 10) reached genome-wide significance and implicated the and genes. Chromosome 6 findings were replicated ( = .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 ( = 1.28 ± 0.38, = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR 1.098, 95% CI 1.046-1.152, < .0001) and BMI (OR 1.129, 95% CI 1.081-1.178, < .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.
儿童遗尿症受到污名化和优先次序较低的影响，且其发病机制基本尚未得到了解。我们的目标是确定日间尿失禁（DUI）相关的风险赋予遗传变异。
我们在丹麦 iPSYCH2015 队列中进行了全基因组关联研究。通过 DUI 诊断代码识别病例（3024 例），并在 5 至 20 岁个体中根据 DUI 药物处方来确认病例。对照组（30240 例）选自同一样本，根据性别和任何精神科诊断与病例相匹配，如果有，则进行降采样，使病例与对照组的比例为 1:10。在冰岛 deCODE 队列中进行了复制（5475 例病例/287773 例对照）。使用基于基因组的受限极大似然法计算单核苷酸多态性遗传力。使用连锁不平衡评分回归估计跨特征的遗传相关性。使用 LDpred2-auto 和 BOLT-LMM 生成的多基因风险评分用于评估关联。
染色体 6（rs12210989，优势比 [OR]1.24，95%CI1.17-1.32， = 3.21×10）和 20（rs4809801，OR1.18，95%CI1.11-1.25， = 3.66×10）达到全基因组显著水平，并提示了 和 基因的作用。染色体 6 的发现得到了复制（ =.024，OR1.09，95%CI1.01-1.16）。 Liability 量表遗传力范围为 10.20%（95%CI6.40%-14.00%）至 15.30%（95%CI9.66%-20.94%）。DUI 和夜间遗尿症显示出正的遗传相关性（ = 1.28±0.38， =.0007）。DUI 与注意力缺陷/多动障碍（OR1.098，95%CI1.046-1.152， <.0001）和 BMI（OR1.129，95%CI1.081-1.178， <.0001）多基因风险相关。
常见的遗传变异导致儿童 DUI 的风险增加，并且涉及到神经元发育和逼尿肌平滑肌活动的重要基因。这些发现可能有助于指导新的治疗靶点的确定。
