Genetic and biological mechanisms of pediatric enuresis: integrating pathophysiology, GWAS associations, and multi-omics research.

Pediatric enuresis is a common developmental disorder involving involuntary nocturnal voiding. This review synthesizes current evidence on its neurodevelopmental, renal, circadian, and genetic underpinnings. Traditional classification into monosymptomatic and non-monosymptomatic forms guides treatment but does not fully capture underlying biological heterogeneity. Genome-wide association studies have identified risk loci on chromosomes 6 and 13, implicating pathways in neuronal signaling, circadian regulation, and renal water handling, though these represent associations rather than proven causal variants. Multi-omics data, including urinary aquaporin-2 levels and neurotransmitter-related metabolites, further highlight disruptions in the brain-bladder-kidney axis. Persistent enuresis beyond school age, especially treatment refractory cases, likely reflects distinct biological endotypes beyond simple maturational delay. Integrating GWAS findings with transcriptomic, proteomic, and metabolomic approaches, alongside advanced computational methods such as polygenic risk scoring, offers promise for precision pediatrics. Future studies should stratify by age, severity, and persistence while combining population-based and clinical cohorts to advance targeted therapies. What is Known: • Pediatric enuresis is a common developmental disorder characterized by involuntary nocturnal urination in children aged ≥ 5 years. • The condition is clinically classified into monosymptomatic nocturnal enuresis (MNE) and non-monosymptomatic nocturnal enuresis (NMNE), which differ in associated lower urinary tract symptoms and treatment approaches. • Existing evidence indicates that enuresis is strongly influenced by neurodevelopmental delay, circadian dysregulation, impaired nocturnal arginine vasopressin (AVP) secretion, altered bladder function, and elevated arousal thresholds during sleep. • Family and twin studies have demonstrated substantial heritability, supporting an important genetic contribution to disease susceptibility. What is New: • This review provides the first comprehensive integration of pediatric enuresis pathophysiology with recent GWAS findings (particularly risk loci on chromosomes 6 and 13) and emerging multi-omics data, framing the disorder within a systems biology "brain-bladder-kidney axis" model. • We highlight biological heterogeneity beyond the classic maturational delay hypothesis, emphasizing that persistent, severe, or treatment refractory enuresis after age 7 likely represents distinct endotypes driven by genetic susceptibility, impaired circadian regulation, and altered neuronal signaling rather than simple developmental lag. • By synthesizing candidate gene studies, GWAS results, neuroimaging, circadian biology, and renal physiology while stressing the need for age- and severity-stratified analyses, this work lays the conceptual foundation for precision pediatrics approaches, including polygenic risk scoring and targeted multi-omics-guided therapies. • We underscore critical methodological gaps in existing literature (e.g., small samples, lack of developmental stratification, and recruitment bias) and propose a unified framework to guide future research combining population-based, family, and tertiary cohorts.