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.
| Original language | English |
|---|---|
| Article number | 61 |
| Pages (from-to) | 61 |
| Journal | Frontiers in Behavioral Neuroscience |
| Volume | 12 |
| DOIs | |
| Publication status | Published - 2018 |
Funding
This works was supported by the Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek, NWO), i.e., the NWO Brain & Cognition Excellence Program (grant 433-09-229) and the Vici Innovation Program (grant 016-130-669 to BF). Additional support was received from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements no 602805 (Aggressotype), no 602450 (IMAGEMEND), and no 278948 (TACTICS) as well as from the European Community's Horizon 2020 Programme (H2020/2014-2020) under grant agreements no 643051 (MiND) and no 667302 (CoCA). The work was also supported by grants for the ENIGMA Consortium (Foundation for the National Institutes of Health (NIH); grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium provided summary statistics of the consortium findings to this project. The original publication of those findings as well as the list of contributing samples and people can befound on the ENIGMA website: http://enigma.ini.usc.edu. The EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium provided summary statistics of the consortium findings to this project. Contributing samples and people can be found in the original publication of those findings (Pappa et al., 2015).
| Funders | Funder number |
|---|---|
| National Institutes of Health | U54 EB020403 |
| Horizon 2020 Framework Programme | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 433-09-229 |
| Seventh Framework Programme | 602805, FP7/2007-2013, 602450, 278948 |
| Horizon 2020 | H2020/2014-2020, 667302, 643051 |