Multiplex gray and white matter networks in autism spectrum disorder: differential topological alterations and transcriptomic associations.
Autism spectrum disorder (ASD) is classically conceptualized as a dysconnectivity syndrome. However, most studies have examined structural and functional connectivity in isolation, leaving the coupling mechanisms between brain structure and function, particularly the contribution of white matter, poorly understood. To systematically characterize connectome pathology in ASD, we analyzed multimodal imaging data from 580 participants (240 with ASD, 340 typical controls) in the Autism Brain Imaging Data Exchange II dataset. We constructed multilayer brain networks integrating gray and white matter layers and quantified topological alterations using multiplex clustering and participation coefficients. Imaging-transcriptomic analysis was performed using the Allen Human Brain Atlas to link network changes to molecular pathways. The results revealed widespread whole-brain topological reorganization in white matter multiplex networks, involving the corpus callosum and major fiber tracts, with gene expression enriched in immune regulation and cellular metabolism pathways. The gray matter multiplex networks exhibited localized hyper-clustering centered on the cortico-striatum-thalamic-cortical circuit and the default mode network associated with genes implicated in cell adhesion and synaptic transmission. Notably, no significant group differences were observed in the multiplex participation coefficient, which indexes cross-layer integration, suggesting that the overall cross-layer connectivity distribution remains relatively stable. These findings delineate the co-occurring patterns of gray matter hyper-clustering and widespread white matter topological alterations in ASD and establish a multilevel framework bridging macroscopic connectome disruptions to the underlying molecular mechanisms, offering an integrated perspective on ASD heterogeneity.