Investigation of brain structures and potential mechanisms associated with ADHD: Insights from Mendelian...

Despite extensive studies linking brain structure with attention deficit hyperactivity disorder (ADHD), the causal relationships remain unclear. This study employs Mendelian randomization (MR) to assess these associations and explores the underlying mechanisms.

Utilizing genetic instruments from genome - wide association study (GWAS) data of 83 magnetic resonance imaging (MRI) studies sourced from the psychiatric genomics consortium (PGC) and integrative epidemiology unit (IEU), MR analyses were conducted to investigate the link between brain structures and ADHD. The Allen Human Brain Atlas was used to identify genes associated with significant brain structures, followed by gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and pathway enrichment analyses, and construction of protein - protein interaction (PPI) networks.

Intersection analysis from two MR studies highlighted 17 brain structures, such as the left caudal and rostral middle frontal volumes and right medial orbitofrontal volume, exhibiting strong negative correlations with ADHD symptoms (FDR < 0.05). These structures span the frontal, temporal, and parietal lobes, among others. Differential expression analysis showed these genes predominantly relate to pervasive developmental and autistic disorders, with functions including modulation of synaptic transmission. KEGG pathways identified neuroactive ligand-receptor interaction as significantly involved. PPI analysis pinpointed key proteins like SLC17A7, CAMK2A, and SST as critical hubs.

This research confirms negative correlations between certain brain structures and ADHD and implicates neuroactive ligand-receptor interactions in its pathogenesis, enhancing our understanding of ADHD's anatomical and genetic bases.