There is a considerable overlap in clinical features and genetics between schizophrenia (SZ) and bipolar disorder (BD). Previous neuroimaging research has demonstrated common and distinct brain damage patterns between relatives (RELs) of SZ and BD patients, suggesting shared and differential genetic influences on the brain. Despite an increasing recognition that disorders localize better to distributed brain networks than individual brain regions, studies investigating network localization of genetic risk for SZ and BD are still lacking.

To address this gap, we initially identified brain functional and structural damage locations in SZ- and BD-RELs from 103 published studies with 2364 SZ-RELs, 864 BD-RELs, and 4114 healthy controls. By applying novel functional connectivity network mapping to large-scale discovery and validation resting-state functional MRI datasets, we mapped these affected brain locations to four disorder-susceptibility networks.

SZ-susceptibility functional damage network primarily involved the executive control and salience networks, while its BD-counterpart principally implicated the default mode and basal ganglia networks. SZ-susceptibility structural damage network predominantly involved the auditory and default mode networks, yet its BD-counterpart mainly implicated the language and executive control networks. Although these networks showed cross-disorder inconsistencies when focusing on either imaging modality alone, the combined SZ- and BD-susceptibility brain damage networks had a substantially increased spatial similarity.

These findings may support the concept that SZ and BD represent distinct diagnostic categories from a neurobiological perspective, helping to clarify the common network substrates via which the shared genetic mechanisms underlying both disorders give rise to their overlapping clinical phenotypes.

Neuroimaging studies have documented brain structural changes in schizophrenia at different stages of the illness, including clinical high-risk (cHR), genetic high-risk (gHR), first-episode schizophrenia (FES), and chronic schizophrenia (ChS). There is growing awareness that neuropathological processes associated with a disease fail to map to a specific brain region but do map to a specific brain network. We sought to investigate brain structural damage networks across different stages of schizophrenia.

We initially identified gray matter alterations in 523 cHR, 855 gHR, 2162 FES, and 2640 ChS individuals relative to 6963 healthy controls. By applying novel functional connectivity network mapping to large-scale discovery and validation resting-state functional magnetic resonance imaging datasets, we mapped these affected brain locations to four specific networks.

Brain structural damage networks of cHR and gHR had limited and non-overlapping spatial distributions, with the former mainly involving the frontoparietal network and the latter principally implicating the subcortical network, indicative of distinct neuropathological mechanisms underlying cHR and gHR. By contrast, brain structural damage networks of FES and ChS manifested as similar patterns of widespread brain areas predominantly involving the somatomotor, ventral attention, and subcortical networks, suggesting an emergence of more prominent brain structural abnormalities with illness onset that have trait-like stability over time.

Our findings may not only provide a refined picture of schizophrenia neuropathology from a network perspective, but also potentially contribute to more targeted and effective intervention strategies for individuals at different schizophrenia stages.