NEURAL MECHANISMS MEDIATING GENE-BEHAVIOR ASSOCIATIONS IN AGGRESSION

Background Aggression is a heterogeneous and heritable (~50%) phenotype, associated with a substantial financial and emotional burden on society. A better understanding of aggression etiology is needed to improve prevention and treatment options. Genome-wide association studies of aggression have identified several regions that may contain genetic risk factors for aggression. Imaging studies indicate that subcortical structures involved in emotion processing and decision making play an important role in aggression etiology. In the current study, we aimed to gain more insight into the mechanisms leading from genetic risk factors for aggression to aggression phenotypes, by evaluating neural correlates mediating gene-behavior associations. Methods We first conducted genome-wide cross-trait meta-analyses of aggression and different brain volume measures, to identify genes influencing both aggression and brain volume. We used data of two large-scale genome-wide association studies of 1) aggressive behavior in children and adolescents (EAGLE, N=18,988) and 2) Magnetic Resonance Imaging (MRI)-based volume measures of aggression-relevant brain regions (ENIGMA2, N=13,171). Competitive gene-wide analyses with a 50 kb flanking region around genes were performed for each phenotype, followed by fixed-effects meta-analyses using the weighted Stouffer's Z method as implemented in MAGMA software. Results The Vasopressin Receptor 1 A gene (AVPR1A) passed the gene-wide threshold (p Discussion Our finding suggests that an effect on amygdala volume may underlie the mechanism through which AVPR1A influences aggressive behavior. AVPR1A codes for the primary receptor of arginine vasopressin (AVP) in the brain, a neuropeptide which has been strongly implicated in complex social and emotional behaviors including aggression. As different subtypes of aggression may be mediated by unique underlying neurocognitive systems, we will follow up by assessing gene-wide association of AVPR1A with subtypes of aggression in our own sample of healthy adults, who have both anatomical MRI data and questionnaire data on aggression subtypes available (BIG, N=703). Additionally, we will use mediation analysis to test whether the observed link between the AVPR1A gene and amygdala volume is relevant for aggressive behavior.