Network localization of genetic risk for schizophrenia and bipolar disorder

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.