Heterogeneity-Aware, Multiscale Annotation of Shared and Specific Neurobiological Signatures among Major...

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) represent major neurodevelopmental disorders with distinct typical ages of onset. These disorders exhibit substantial genetic and phenotypic overlap, yet their shared and disorder-specific neurobiological mechanisms remain unclear. We analyzed resting-state functional magnetic resonance imaging data from 2,176 participants (ASD, ADHD, SCZ, and healthy controls). Using heterogeneous matrix factorization, we extracted meta-blood-oxygen-level-dependent signals to reduce individual heterogeneity and constructed functional connectivity networks. Partial least squares identified a shared transdiagnostic abnormal connectivity pattern (STACP) and disorder-specific connectivity deviations (DSCDs). We annotated edges with transcriptomic, neurotransmitter, and mitochondrial maps for biological interpretation. The STACP involved connections linking deep regulatory systems (cerebellum, brain stem, and subcortical network) and cortical perceptual-executive networks (default mode, visual, frontoparietal, and somatomotor). The DSCDs of ASD and ADHD implicated overlapping networks with opposite functional connectivity directions (decreased in ASD and increased in ADHD), while SCZ showed more widespread desynchronization. STACP-related genes were enriched for synaptic development, cytoskeletal remodeling, and lipid metabolism, expressed in midbrain and deep-layer cortical neurons, and associated with serotonin transporter and cytochrome c oxidase. DSCDs were linked to glutamatergic plasticity and immune activation in ASD, dopaminergic regulation and glia-neuron interactions in ADHD, and broad synaptic plus immune-metabolic dysregulation in SCZ. Together, these findings provide a systems-level characterization of shared and disorder-specific neurobiological features across major neurodevelopmental disorders observed at different life stages.