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Front Behav Neurosci. 2018 Apr 3;12:61. doi: 10.3389/fnbeh.2018.00061. eCollection 2018.

Pleiotropic Contribution of MECOM and AVPR1A to Aggression and Subcortical Brain Volumes.

Author information

1
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
2
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands.
3
Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Rotterdam, Netherlands.
4
Department of Psychiatry, Erasmus Medical Center, Rotterdam, Netherlands.
5
Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
6
Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands.
7
Karakter Child and Adolescent Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands.
8
Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands.

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.

KEYWORDS:

MRI; aggression; brain imaging; genetics; neurobiology

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