Abstract
Reactive and proactive subtypes of aggression have been recognized to help parse etiological heterogeneity of this complex phenotype. With a heritability of about 50%, genetic factors play a role in the development of aggressive behavior. Imaging studies implicate brain structures related to social behavior in aggression etiology, most notably the amygdala and striatum. This study aimed to gain more insight into the pathways from genetic risk factors for aggression to aggression phenotypes. To this end, we conducted genome-wide gene-based cross-trait meta-analyses of aggression with the volumes of amygdala, nucleus accumbens and caudate nucleus to identify genes influencing both aggression and aggression-related brain volumes. We used data of large-scale genome-wide association studies (GWAS) of: (a) aggressive behavior in children and adolescents (EAGLE, N = 18,988); and (b) Magnetic Resonance Imaging (MRI)-based volume measures of aggression-relevant subcortical brain regions (ENIGMA2, N = 13,171). Second, the identified genes were further investigated in a sample of healthy adults (mean age (SD) = 25.28 (4.62) years; 43% male) who had genome-wide genotyping data and questionnaire data on aggression subtypes available (Brain Imaging Genetics, BIG, N = 501) to study their effect on reactive and proactive subtypes of aggression. Our meta-analysis identified two genes, MECOM and AVPR1A, significantly associated with both aggression risk and nucleus accumbens (MECOM) and amygdala (AVPR1A) brain volume. Subsequent in-depth analysis of these genes in healthy adults (BIG), including sex as an interaction term in the model, revealed no significant subtype-specific gene-wide associations. Using cross-trait meta-analysis of brain measures and psychiatric phenotypes, this study generated new hypotheses about specific links between genes, the brain and behavior. Results indicate that MECOM and AVPR1A may exert an effect on aggression through mechanisms involving nucleus accumbens and amygdala volumes, respectively.
Highlights
Aggression is a common but heterogeneous phenotype often associated with psychiatric disorders that may be harmful to others (Baron and Deborah, 1994; Miczek et al, 2002)
Gene-wide association analyses with three aggression subtypes were conducted for AVPR1A and MECOM to identify gene-behavior relationships, including sex as an interaction term in the model
We identified MECOM as a gene potentially contributing to both aggression risk and nucleus accumbens volume, and we identified AVPR1A as a gene potentially contributing to both aggression risk and amygdala volume
Summary
Aggression is a common but heterogeneous phenotype often associated with psychiatric disorders that may be harmful to others (Baron and Deborah, 1994; Miczek et al, 2002). Heritability estimates differ as a function of the population and the type of aggression that is investigated, twin studies show that about 50% of the variance in aggression can be explained by genetic influences, implicating a role for genetics in the development of aggressive behavior (Tuvblad and Baker, 2011; Veroude et al, 2016). Despite this considerable heritability of aggression, the identification of specific genetic risk factors has been difficult. While most other GWASs of aggression were relatively small-scaled, top-finding of these studies together with bioinformatics approaches have highlighted the importance of neurodevelopmental and synaptic plasticity genes for aggression risk (Fernàndez-Castillo and Cormand, 2016)
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