Abstract Objectives ULK4 is an established candidate gene for mental disorders and antipsychotic treatment response and codes for a serine/threonine kinase that regulates the neural stem cell pool and controls cortex development. We investigated the effects of functional genetic variation at the ULK4 locus on the human extended dopaminergic reward system using functional magnetic resonance imaging (fMRI) during performance of a well-established reward paradigm. Methods 234 study participants with functional neuroimaging (fMRI) data of the extended reward system and with ULK4 genotype data were included in this study. Effects of genetic variation in the ULK4 gene on reward system functioning were determined using the Desire-Reason-Dilemma (DRD) paradigm which allows to assess brain activation in response to conditioned reward stimuli (Diekhof et al. 2010). Results Among common missense variants of the ULK4 gene, variant prioritization revealed strongest functional signatures for variant rs17215589, coding for amino acid exchange Ala715Thr. For rs17215589 minor allele carriers, we detected increased activation responses to conditioned reward stimuli in the ventral tegmental area, the nucleus accumbens and several cortical brain regions of the extended reward system. Conclusions Our findings provide further evidence in humans that genetic variation in ULK4 may increase the vulnerability to mental disorders by modulating the function of the extended reward system. Future studies are needed to confirm the functional modulation of the extended reward system by ULK4 and to specify the role of this mechanism in the pathogenesis of psychiatric disorders.

Impact of Unc-51 Like Kinase 4 (ULK4) on the Reactivity of the Extended Reward System in Response to Conditioned Stimuli