Autism Spectrum Disorder–Associated Genes Enrich in Discrete Cortical, Limbic and Cerebellar Brain Regions

Abstract

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental condition with a well-characterised genetic architecture, yet how ASD-associated genes map onto discrete brain regions remains poorly understood. This study applied a recently validated analysis pipeline (ATLANTE) to discover regions of the human brain enriched for high expression of 234 high-confidence ASD-associated genes. Eleven discrete brain regions were identified, spanning cortical, limbic and cerebellar systems including the anterior orbitofrontal gyrus, cerebellar cortex, flocculonodular lobe, vermis, posterior cingulate cortex, temporo-occipital transitional zone, hippocampal subfields CA1 and CA3, postcentral gyrus, occipital cortex and perirhinal gyrus. Notably, the anterior orbitofrontal gyrus exhibited significant enrichment for syndromic ASD genes, suggesting a core role in the neuropsychiatric features of syndromic presentations. Network and community clustering analyses revealed three major gene communities corresponding to distinct biological processes: synaptic dysfunction in limbic regions, histone modification in cerebellar regions and axonal ion channel regulation in cortical regions. Nodal analysis identified eight high-priority genes with broad relevance across multiple brain regions, including NR3C2, GABRB2 and NBEA. These findings provide a refined neuroanatomical framework for ASD pathophysiology, identify understudied brain regional targets and imply that ASD-associated genes exert primary effects in specific brain regions.