Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; National Centre for Register-based Research (NCRR), Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark; Center for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark.
Lancet Child Adolesc Health. 2021 Mar;5(3):201-209. doi: 10.1016/S2352-4642(20)30350-3. Epub 2021 Jan 15.
Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology.
We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis.
The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10). All associated variants in the chromosome 6 locus were replicated (p<8 × 10) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target.
This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.
遗尿症（尿床）是一种常见疾病，影响全球 7 岁儿童的 10%-16%。遗尿症具有高度遗传性，但其遗传决定因素尚不清楚。我们旨在确定与遗尿症相关的遗传变异，并探索其遗传结构和潜在生物学。
我们对遗尿症进行了全基因组关联研究（GWAS）。遗尿症病例是在基于第 10 次修订的《国际疾病分类》（ICD-10）诊断的大型丹麦基于人群的病例队列 iPSYCH2012 中确定的，该队列旨在调查精神障碍，并在丹麦登记处使用去氨加压素处方进行了 redeemed。GWAS 在遗传上同质的无关个体样本中使用逻辑回归进行，带有相关协变量。所有全基因组显著变异均在 deCODE genetics 的独立冰岛样本中进行了与遗尿症相关的分析。从大型 GWAS 的汇总统计数据构建了注意力缺陷多动障碍（ADHD）和自闭症谱系障碍的标准化多基因风险评分，并对其与遗尿症的相关性进行了分析。
GWAS 纳入了 3882 例遗尿症病例和 31073 例对照。我们发现染色体 6 和染色体 13 上的两个位点与遗尿症显著相关。两个位点的六个遗传变异（染色体 6q16.2 上的五个变异和染色体 13q22.3 上的一个变异）超过了全基因组显著水平的阈值（p<5×10）。有两个主要变异：rs9376454（染色体 6q16.2），优势比（OR）为 1.199（95%CI 1.135-1.267;p=9.91×10），rs60721117（染色体 13q22.3），OR 为 1.149（1.095-1.205;p=1.21×10）。染色体 6 位点的所有相关变异均在独立的 5475 例遗尿症病例和 303966 例对照的冰岛队列中得到复制（p<8×10），而染色体 13 位点的相关变异则显示出名义上的显著关联（p=0.031）。常见遗传变异解释的遗尿症表型变异的百分比为 23.9-30.4%。ADHD 的多基因风险与遗尿症相关（OR 1.06，95%CI 1.01-1.10;p=0.011）。在所映射的潜在遗尿症风险基因中，PRDM13 和 EDNRB 具有与遗尿症已知病理生理机制相关的生物学功能，而 SIM1 调节产生精氨酸加压素的下丘脑神经内分泌谱系的形成，精氨酸加压素是一种众所周知的遗尿症药物靶点。
这项研究表明，常见的遗传变异对遗尿症有很大的贡献，并确定了潜在的遗尿症风险基因，这些基因在睡眠、尿液产生和膀胱功能中发挥作用。鉴于现有治疗方法针对这些机制，任何已确定的基因及其功能基因网络都可能成为药物靶点。
Lundbeck Foundation Initiative for Integrative Psychiatric Research（iPSYCH），Stanley Foundation。
