Targeting glutamatergic pathways: genetic insights into comorbid neurodevelopmental disorders

Copy number variants (CNVs) in genes encoding metabotropic glutamate receptors (GRMs) have been previously implicated in attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, investigations of their role in comorbid ADHD patients suffering from coexisting neurodevelopmental disorders (NDDs), such as anxiety and ASD with or without developmental delay remains limited. To assess the enrichment of CNVs in GRM genes and their molecular interaction networks in a large pediatric cohort with ADHD and comorbid NDDs, we analyzed CNV data from 72,626 pediatric participants recruited through the Center for Applied Genomics at Children's Hospital of Philadelphia. The cohort includes 12,472 individuals diagnosed with ADHD (including 7,967 with other NDD comorbid conditions). CNVs were identified using PennCNV and annotated for overlap with GRM genes and their protein-protein interaction (PPI) networks using data from STRING. We evaluated CNV enrichment in ADHD cases with and without comorbid diagnoses, including autism spectrum disorder (ASD), anxiety, and developmental delay. Significant enrichment of CNVs was observed in GRM-interacting networks among ADHD cases with comorbid NDDs. Specifically, 27 genes interacting with primary GRM genes were significantly enriched in CNVs in these individuals with false discovery rate (FDR) < 0.05, compared to ADHD-only cases or disease-free controls. These included key neurodevelopmental genes such as DLG2, NRXN1, SHANK3, and SYNGAP1, which are involved in synaptic signaling and glutamatergic neurotransmission. In contrast, enrichment of GRM network gene CNVs observed in ADHD-only cases was notably less. Our findings support a distinct genetic profile in ADHD cases with comorbid NDDs, marked by CNV enrichment in glutamatergic signaling pathways involving GRM-interacting genes. These results suggest that GRM network disruptions contribute to the complexity of the phenotype spectrum in ADHD patients suffering from comorbid neurodevelopmental phenotypes and highlight a potential pathway for targeted, genetically informed interventions in these patients.