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

IF 5.9 2区医学 Q1 UROLOGY & NEPHROLOGY Journal of Urology Pub Date : 2024-12-01 Epub Date: 2024-08-02 DOI:10.1097/JU.0000000000004187

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

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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.

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探索儿童日间尿失禁的遗传风险：全基因组关联研究

目的：儿童尿失禁是一种耻辱，未得到足够重视，对其发病机制也缺乏基本了解。我们的目标是确定日间尿失禁（DUI）的风险诱导基因变异：我们在丹麦 iPSYCH2015 队列中开展了一项全基因组关联研究。病例（3024 例）是通过 5 至 20 岁儿童的白天尿失禁诊断代码和赎回的白天尿失禁药物处方确定的。对照组（30,240 人）从同一样本中选出，与病例的性别和精神诊断（如有）相匹配，并按病例与对照组 1:10 的比例向下取样。在冰岛 deCODE 队列（5475 例病例/287773 例对照）中进行了复制。采用基于基因组的限制性最大似然法计算单核苷酸多态性遗传率。跨性状遗传相关性采用连锁不平衡得分回归法进行估算。利用 LDpred2-auto 和 BOLT-LMM 生成的多基因风险评分对关联性进行了评估：结果：6 号染色体（rs12210989，OR = 1.24 [95% CI：1.17-1.32]，P = 3.21 × 10-12）和 20 号染色体（rs4809801，OR = 1.18 [95% CI：1.11-1.25]，P = 3.66 × 10-8）上的变异达到全基因组显著性，与 PRDM13 和 RIPOR3 基因有关。6 号染色体的研究结果得到了重复（P = 0.024，OR = 1.09 [95% CI：1.01-1.16]）。责任量表遗传率从 10.20% (95% CI: 6.40%-14.00%) 到 15.30% (95% CI: 9.66%-20.94%) 不等。DUI和夜遗尿显示出正遗传相关性（rg = 1.28 ± 0.38，P = .0007）。DUI与注意力缺陷/多动障碍（OR = 1.098 [95% CI: 1.046-1.152]，P < .0001）和体重指数（OR = 1.129 [95% CI: 1.081-1.178]，P < .0001）多基因风险相关：结论：常见的基因变异会导致儿童酒后驾车的风险，其中牵涉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确定新的治疗目标。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Urology 医学-泌尿学与肾脏学

CiteScore

11.50

自引率

7.60%

发文量

3746

审稿时长

2-3 weeks

期刊介绍： The Official Journal of the American Urological Association (AUA), and the most widely read and highly cited journal in the field, The Journal of Urology® brings solid coverage of the clinically relevant content needed to stay at the forefront of the dynamic field of urology. This premier journal presents investigative studies on critical areas of research and practice, survey articles providing short condensations of the best and most important urology literature worldwide, and practice-oriented reports on significant clinical observations.