Targeting glutamatergic pathways: genetic insights into comorbid neurodevelopmental disorders

Area of Science:

• Neurogenetics
• Developmental Neuroscience
• Genomic Medicine

Background:

• Copy number variants (CNVs) in metabotropic glutamate receptor (GRM) genes are associated with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).
• Limited research exists on CNVs in GRM genes within ADHD patients who have comorbid neurodevelopmental disorders (NDDs) like anxiety and ASD.

Purpose of the Study:

• To investigate the enrichment of CNVs in GRM genes and their associated molecular interaction networks.
• To analyze a large pediatric cohort with ADHD and comorbid NDDs to understand genetic contributions to complex neurodevelopmental phenotypes.

Main Methods:

• Analyzed CNV data from 72,626 pediatric participants, including 12,472 with ADHD (7,967 with comorbid NDDs).
• Identified CNVs using PennCNV and annotated them for overlap with GRM genes and protein-protein interaction (PPI) networks via STRING.
• Evaluated CNV enrichment in ADHD cases with and without comorbid diagnoses (ASD, anxiety, developmental delay) versus controls.

Main Results:

• Significant enrichment of CNVs was found in GRM-interacting networks in ADHD cases with comorbid NDDs (FDR < 0.05).
• 27 genes interacting with primary GRM genes showed significant CNV enrichment, including key neurodevelopmental genes like DLG2, NRXN1, SHANK3, and SYNGAP1.
• CNV enrichment in GRM network genes was less pronounced in ADHD-only cases compared to those with comorbid conditions.

Conclusions:

• ADHD patients with comorbid NDDs exhibit a distinct genetic profile characterized by CNV enrichment in glutamatergic signaling pathways.
• Disruptions in GRM network genes contribute to the complex phenotype spectrum observed in ADHD with comorbid neurodevelopmental disorders.
• Findings suggest potential for targeted, genetically informed interventions for this patient group.