Interactome modules underlie shared spatiotemporal patterns in specific psychiatric and neurodegenerative disorders

Psychiatric and neurological clinical syndromes show considerable overlap, and these have been largely captured by genetic correlation studies. Detailed, hypothesis-generating investigations into the transcriptomic and interactome patterns of risk-related genes, particularly that of their first-order interactors, are lacking. In this study, we examined brain spatiotemporal expression and interactome patterns of risk genes associated with five syndromes with overlapping symptom clusters: obsessive-compulsive disorder (OCD), Huntington’s disease (HD), Parkinson’s disease (PD), schizophrenia (SZ), and bipolar disorder (BD). The disease gene set, when taken alone, showed no significant interconnectivity in the interactome. However, inclusion of first-order interactors revealed extensive connectivity, exceeding degree-matched random expectations, indicating that the disease genes are embedded within cohesive subnetworks. This enrichment persisted after hub removal, suggesting connectivity is driven by distributed, disease-relevant interactions, rather than global network structure. At the network level, OCD showed a prenatal expression signature with enrichment in foetal structures. Interestingly, the network expression profile of PD, a late-onset syndrome, resembled that of OCD, which presents earlier in life. Further analyses showed that these co-expression signals did not come uniformly from the full syndrome networks, but from groups of highly interconnected proteins that formed specific PD and OCD network modules, and occurred in close proximity in the interactome. They show a prenatal expression signature in the developing prefrontal cortex, and share enrichment for ribosome-related processes. Together, our findings support a network-based model of brain disorders in which genetic risks act through distributed, yet coherent, modules which are organised across brain regions and developmental time periods.