Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study.

Attention Deficit Disorder with Hyperactivity / genetics Autism Spectrum Disorder / genetics Child Chromosomes, Human, Pair 13 / genetics Chromosomes, Human, Pair 6 / genetics Deamino Arginine Vasopressin / therapeutic use Female Genetic Loci / genetics Genetic Variation / genetics Genome-Wide Association Study Humans Male Nocturnal Enuresis / drug therapy Phenotype

Journal

The Lancet. Child & adolescent health

ISSN: 2352-4650

Titre abrégé: Lancet Child Adolesc Health

Pays: England

ID NLM: 101712925

Informations de publication

Date de publication:
03 2021

Historique:

received: 06 09 2020

revised: 27 10 2020

accepted: 03 11 2020

pubmed: 18 1 2021

medline: 19 3 2021

entrez: 17 1 2021

Statut: ppublish

Résumé

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 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.

Sections du résumé

BACKGROUND

METHODS

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.

FINDINGS

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

INTERPRETATION

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.

FUNDING

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.

Identifiants

DOI: 10.1016/S2352-4642(20)30350-3 PMID: 33453761

pubmed: 33453761

pii: S2352-4642(20)30350-3

doi: 10.1016/S2352-4642(20)30350-3

pii:

doi:

Substances chimiques

Deamino Arginine Vasopressin ENR1LLB0FP

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

201-209

Subventions

Organisme : NIMH NIH HHS

ID : U01 MH109514

Pays : United States