Sulcal Widening in Schizophrenia Maps onto Sulcal Hubs and Energy-Synaptic Genes

Abstract

Schizophrenia (SZ) is increasingly framed as a disorder of large-scale brain networks emerging from atypical early neurodevelopment, yet how network architecture relates to cortical folding abnormalities remains unclear. Here, we introduce a sulcal morphological-centred network framework that integrates normative modelling of sulcal width with diffusion-derived structural connectivity and transcriptomic data in a large multisite cohort (n = 5,392; 377 SZ). Individuals with SZ showed widespread sulcal widening, affecting 30 of 40 sulci and most pronounced in frontal, temporal and occipital regions. Critically, sulci with higher degree centrality, reflecting greater embedding within the structural connectome, exhibited disproportionately greater widening in SZ (pspin = 0.02), indicating that network hubs of cortical folding are preferentially affected. Transcriptomic integration using partial least squares regression identified a single component explaining 56.5% of SZ-related sulcal widening variance (pperm = 0.041), implicating genes enriched for synaptic signalling and energy metabolism with adult cortical expression bias and genetic enrichment for cross-disorder psychiatric risk. In contrast, oppositely weighted genes showed prenatal expression bias and enrichment for rare disruptive variants in autism spectrum disorder. Together, these findings link aberrant sulcal morphology in SZ to the brains network topology and molecular architecture, positioning cortical folding as a network-embedded phenotype in SZ.