Macroscale white matter pathways are the infrastructure for large-scale communication in the human brain and a prerequisite for healthy brain function. Disruptions in the brain’s connectivity architecture play an important role in many psychiatric and neurological brain disorders. Here we show that connections important for global communication and network integration are particularly vulnerable to brain alterations across multiple brain disorders. We report on a cross-disorder connectome study comprising in total 1,033 patients and 1,154 matched controls across 8 psychiatric and 4 neurological disorders. We extracted disorder connectome fingerprints for each of these 12 disorders and combined them into a ‘cross-disorder disconnectivity involvement map’ describing the level of cross-disorder involvement of each white matter pathway of the human brain network. Network analysis revealed connections central to global network communication and integration to display high disturbance across disorders, suggesting a general cross-disorder involvement and the importance of these pathways in normal function.