Background: Recently, genome-wide significant risk variants for psychotic disorders have been discovered that afford an opportunity to establish neural mechanisms linked to genetic risk for schizophrenia and bipolar disorder through an imaging genetics approach. Methods: We use an imaging genetics approach in a sample of healthy German volunteers of German descent and a replication sample of similar ethnicity, recruited and assessed with a cognitive and resting fMRI and structural imaging battery in the context of the BMBF-founded MooDs project. Results: ZNF804A and CACNA1C impact on cortical-subcortical connectivity with emphasis on hippocampus and prefrontal cortex. Cognitively specific and global abnormalities can be dissociated, indicating structural (maturational?) components and connectivity aspects relating to the specific type of information processed (working memory, theory of mind, episodic memory, emotional regulation). Discussion: Genome-wide significant variants impact on the brain connectome, partially recapitulating phenotypes observed in patients at risk and with overt disease. Disturbances of connectivity are likely part of the core neurogenetic risk architecture of schizophrenia.