An integrated analysis of genes and functional pathways for aggression in human and rodent models

Abstract

Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models and two sets of genes with causal evidence from Online Mendelian Inheritance in Man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly-interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression.

Association between Soft Drink Consumption and Aggressive Behaviour among a Quarter Million Adolescents from 64 Countries Based on the Global School-Based Student Health Survey (GSHS)

“…Food culture difference may also explain the heterogeneity. Genetic determinants play critical roles in modulating aggressive behavior [13][14][15]. Thus, the heterogeneity observed in our study could be partly due to the difference of genetic background in different countries.…”

Converging roles of glutamate receptors in domestication and prosociality

“…Alterations to the HPA axis are considered to be essential for the emergence of tameness in different (indeed competing) theories of domestication [16,54]. Glutamatergic signaling acts as a prominent regulator of HPA activity and has been identified among the top enriched pathways across studies of aggression [6,55,56,57]. The association of kainate and Group II/III metabotropic receptor genes with multiple stress disorders implicates them in altered HPA-axis activity.…”

Omics Application in Animal Science—A Special Emphasis on Stress Response and Damaging Behaviour in Pigs

“…A gene expression study in blood allowed the identification of a set of six genes necessary to discriminate obsessive–compulsive disorder from other psychiatric disorders (schizophrenia or depression) and from controls with an accuracy of 86% [ 144 ]. In order to gain power to identify candidate genes, GWAS and transcriptomic data obtained in humans and mice have been combined to study aggressive behaviour [ 145 ]. Significantly enriched biological pathways across species were supplemented with phenotypic information to define a ranked list of genes involved [ 145 ].…”