666. ADHD: genes and risk for other conditions

Abstract

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder characterized by substantial clinical heterogeneity and frequent comorbidity with sleep disturbances, inflammatory conditions, and metabolic dysregulation. While ADHD has traditionally been conceptualized as a disorder of cognitive control and reward processing, accumulating evidence suggests that broader biological systems—including circadian regulation, immune signaling, and metabolic pathways—play a critical role in its pathophysiology. However, how genetic liability for ADHD converges with these systems across development remains insufficiently understood. Aims & Objectives This presentation aims to clarify the biological heterogeneity of ADHD by integrating evidence from longitudinal cohort studies and large-scale genetic analyses. Specifically, we seek to identify shared genetic pathways linking ADHD with circadian, inflammatory, and metabolic traits, to examine early-life gene–environment interactions shaping symptom trajectories, and to discuss translational implications for prevention and intervention. Method We synthesize findings from multiple population-based and genetic epidemiological studies, including genome-wide association studies (GWAS) of ADHD and related traits, together with data from a longitudinal birth cohort in Japan. Analytical approaches include polygenic risk score (PRS) analyses, linkage disequilibrium score regression, Mendelian randomization, gene-set enrichment analysis, and structural equation modeling. Key biological domains examined are circadian regulation (melatonin secretion and chronotype), immune and inflammatory processes (perinatal cytokines), and metabolic signaling (adiponectin). ADHD symptoms were assessed longitudinally to capture developmental trajectories. Results Across studies, ADHD showed significant genetic overlap with circadian traits, including reduced melatonin secretion and evening chronotype, with evidence for bidirectional causal relationships. Higher polygenic liability for ADHD predicted delayed sleep onset and longer sleep induction time in children, while genetic liability for evening chronotype was associated with greater ADHD symptom severity. Immune-related mechanisms emerged as a central biological component linking circadian and developmental findings. Gene-set analyses consistently highlighted shared immune and cytokine-related pathways across ADHD and circadian traits. In addition, perinatal inflammation independently increased ADHD symptom severity and significantly amplified the effect of ADHD polygenic risk, indicating a robust gene–environment interaction operating early in development. Finally, in the metabolic domain, lower cord blood adiponectin levels were associated with higher ADHD symptoms and worsening symptom trajectories. Genetic liability for ADHD showed a negative association with adiponectin levels, linking ADHD risk to metabolic regulation and long-term physical health vulnerability. Discussion & Conclusions These findings support a biologically integrative model of ADHD in which circadian, immune, and metabolic processes interact with genetic liability across development. Genetic overlap with circadian traits indicates that altered sleep timing and melatonin regulation are core components of ADHD biology rather than secondary consequences. Immune dysregulation, particularly during the perinatal period, appears to play a key role in amplifying genetic risk and shaping developmental trajectories. Metabolic alterations, reflected by reduced adiponectin levels, further link ADHD genetic liability to later physical health vulnerability. Together, these results underscore the value of biologically informed stratification of ADHD and point toward prevention-oriented strategies targeting sleep regulation, immune balance, and metabolic health alongside core behavioral symptoms.