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
{"title":"探索儿童日间尿失禁的遗传风险：全基因组关联研究","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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).</p><p><strong>Materials and methods: </strong>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.</p><p><strong>Results: </strong>Variants on chromosome 6 (rs12210989, odds ratio [OR] 1.24, 95% CI 1.17-1.32, <i>P</i> = 3.21 × 10<sup>-12</sup>) and 20 (rs4809801, OR 1.18, 95% CI 1.11-1.25, <i>P</i> = 3.66 × 10<sup>-8</sup>) reached genome-wide significance and implicated the <i>PRDM13</i> and <i>RIPOR3</i> genes. Chromosome 6 findings were replicated (<i>P</i> = .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 (<i>r</i><sub><i>g</i></sub> = 1.28 ± 0.38, <i>P</i> = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR 1.098, 95% CI 1.046-1.152, <i>P</i> < .0001) and BMI (OR 1.129, 95% CI 1.081-1.178, <i>P</i> < .0001) polygenic risk.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":17471,"journal":{"name":"Journal of Urology","volume":" ","pages":"851-861"},"PeriodicalIF":5.9000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploring the Genetic Risk of Childhood Daytime Urinary Incontinence: A Genome-Wide Association Study.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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).</p><p><strong>Materials and methods: </strong>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.</p><p><strong>Results: </strong>Variants on chromosome 6 (rs12210989, odds ratio [OR] 1.24, 95% CI 1.17-1.32, <i>P</i> = 3.21 × 10<sup>-12</sup>) and 20 (rs4809801, OR 1.18, 95% CI 1.11-1.25, <i>P</i> = 3.66 × 10<sup>-8</sup>) reached genome-wide significance and implicated the <i>PRDM13</i> and <i>RIPOR3</i> genes. Chromosome 6 findings were replicated (<i>P</i> = .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 (<i>r</i><sub><i>g</i></sub> = 1.28 ± 0.38, <i>P</i> = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR 1.098, 95% CI 1.046-1.152, <i>P</i> < .0001) and BMI (OR 1.129, 95% CI 1.081-1.178, <i>P</i> < .0001) polygenic risk.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":17471,\"journal\":{\"name\":\"Journal of Urology\",\"volume\":\" \",\"pages\":\"851-861\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Urology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/JU.0000000000004187\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/2 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Urology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/JU.0000000000004187","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/2 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
Exploring the Genetic Risk of Childhood Daytime Urinary Incontinence: A Genome-Wide Association Study.
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 (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 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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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.
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