Large-Scale Study Identifies Genes That Increase the Risk of Bedwetting

A team of scientists from Aarhus University (AU) and Aarhus University Hospital (AUH) has identified genetic variants that increase the likelihood of nocturnal enuresis (NE) – commonly referred to as bedwetting. The study is published in the journal The Lancet Child & Adolescent Health.¹

What is nocturnal enuresis?

Wetting the bed is a common occurrence in young children. Typically, it stops between the ages of five to six years – but that is not always the case. NE is defined as repeated, involuntary voiding of urine whilst asleep, occurring after five years of age. It is reported to affect ~16% of seven-year-old children, and a small percentage of young adults. The impact of NE on a child or young adult's psychological wellbeing, self-esteem and quality of life can be severe.

Since the 1930s, science has sought to identify exactly why some children wet the bed after a certain age, whilst others do not. Evidence thus far shows us that whilst there is no single factor that causes bedwetting after the age of five, genetics is an important contributor.²

"In the 1990s, Eiberg and co-workers (and other research groups later on) studied extended families where NE was segregating in many generations. They found certain genomic regions on chromosome four, eight, 12, 13 and 22 linked to the condition, however they did not identify any specific genes or risk variants causing it," Jane Hvarregaard Christensen, associate professor in the department of biomedicine at AU, told Technology Networks.

Christensen is the leader of a new study published in The Lancet Child & Adolescent Health that has successfully identified several genetic variants that increase the risk of NE.

Identifying genetic risk factors for NE

The team opted for a genome-wide association study (GWAS) methodology. This approach – commonly used in genetics research – involves scanning whole genomes to identify genetic variants that may be associated, or correlated, with a particular phenotype.

The scientists analyzed the genomes of ~3,900 Danish children and young people that had received a diagnosis of NE or had taken medication for it. The findings were then compared to the genomes of a control group including 31,000 children or young people.

Christensen and colleagues identified two loci (areas) in the genome that are associated with NE – one at chromosome six, and the other at chromosome 13. The specific risk variants within these areas were mapped to 12 protein-coding genes in total. Three of these genes were of particular interest to the researchers: PRDM13, SIM1 and EDNRB.

"PRDM13 (on chromosome six) is a gene that is important for the development of the central nervous system, specifically the regulation of the balance of inhibitory and excitatory neurons. Thus, one could speculate that PRDM13 affects the maturation of the brain regions responsible for the regulation of sleep, regulation of the nightly urine production or for the networks integrating the signals from the bladder," Christensen said. PRDM13 has been demonstrated as important in regulating sleep patterns in mice.

SIM1 encodes a protein that is essential in regulating the layout of neurons that produce the antidiuretic hormone arginine vasopressin (AVP). "AVP is a hormone that is essential for the lowering of the urine production during sleep, and an effective and widespread treatment of NE is a drug substituting this effect, namely desmopressin (Minirin)," added Christensen.

EDNRB encodes the endothelin receptor, which has a variety of roles in the human body – several of which are relevant to NE. EDNRB is involved in the regulation of salt excretion and the elimination of water from the body. Christensen noted that the potential roles of EDNRB in smooth muscle and detrusor contraction "could relate to eventual bladder dysfunction in NE".

The scientists decided to corroborate their findings by analyzing the genetic data of an independent Icelandic cohort in collaboration with deCODE genetics. The sample included 5475 NE cases and 303,996 controls, and all associated variants found on chromosome six were replicated in this cohort. This additional level of analysis adds to the robustness of the study findings, Christensen said.

Shared etiology

The scientists also looked for evidence of shared etiology (causation) between NE and other behavioral disorders, such as attention deficit hyperactivity disorder (ADHD) and Autism spectrum disorder.

Findings show that a child with greater genetic risk for ADHD has an increased vulnerability to bedwetting. This does not mean to say that ADHD causes bedwetting, as the authors emphasize in the paper: "We found no indication that the associations were driven by these neurodevelopmental disorders, because all six identified variants had a robust association with NE when individuals with psychiatric diagnoses were excluded."

Towards further understanding and a treatment?

NE is a complex condition, Christensen emphasized, and it is not possible to identify a singular gene that causes it. Nonetheless, identifying potential contributing factors to a condition is a key component in the journey to an effective therapeutic. This study paves the way for identifying genes that could be potential drug targets for the condition in the future.

There are limitations to the work that will need to be addressed in further studies. The sample is exclusively Northern European, Christensen highlighted. "It will be important in the future to study other NE cases in other populations to see whether they share the same genetic risk, or whether there are differences," she said. "Our immediate next steps will be to study even larger samples. These are expected to reveal further insight into the genetic risk and will also make it possible for us to study the genetic correlation between NE and some of the well-known comorbidities, such as daytime urinary incontinence."

Jane Hvarregaard Christensen was speaking to Molly Campbell, Science Writer, Technology Networks.

References:

1.       Jørgensen CS, Horsdal HT, Rajagopal VM, et al. Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study. The Lancet Child & Adolescent Health. 2021. doi:10.1016/S2352-4642(20)30350-3.

2.       von Gontard A, Schaumburg H, Hollmann E, Eiberg H, Rittig S. The genetics of enuresis: a review. J Urol. 2001;166(6):2438-2443. doi:10.1097/00005392-200112000-00117.