Comparative Genomic and Clinical Analysis of Empathy and Aggression-Related Genes in Mice and Humans: Evidence from Large-Scale Databases and Translational Studies

Abstract

Background: Understanding the genetic architecture underlying prosocial and antisocial behaviors is critical for advancing translational psychiatry. Both empathy and aggression represent complex behavioral phenotypes with conserved evolutionary mechanisms across mammalian species, yet their genetic underpinnings remain incompletely characterized.

Objectives: This study conducted a comprehensive comparative genomic analysis of empathy-associated and violence-related genes between Mus musculus and Homo sapiens, integrating data from large-scale genomic databases, genome-wide association studies (GWAS), and clinical psychiatric databases to elucidate conserved molecular pathways and translational validity of mouse models.

Methods: We performed systematic analysis of candidate genes implicated in empathy (OXTR, AVPR1A, CD38) and aggression (MAOA, SLC6A4/5-HTT, DRD2) by comparing sequences across species, examining conservation of regulatory regions, and analyzing expression patterns. Clinical data were extracted from psychiatric databases including studies on antisocial personality disorder, autism spectrum disorders, and conduct disorders (n>50,000 subjects across multiple cohorts). Mouse knockout models and human genetic association studies were synthesized to establish genotype-phenotype correlations.

Results: Comparative genomic analysis revealed high conservation of empathy-related genes: OXTR (92% amino acid sequence similarity), CD38 (88% similarity), and AVPR1A (90% similarity) between mice and humans, with conserved promoter regions showing 85-90% homology. Violence-associated genes demonstrated similar conservation: MAOA (95% similarity) and 5-HTT/SLC6A4 (94% similarity). GWAS meta-analyses (N=47,000+) identified OXTR rs53576 polymorphism significantly associated with emotional empathy (p=1.2×10⁻⁸), while CD38 rs3796863 correlated with autism-related social deficits (p=3.4×10⁻⁷). For aggression genes, MAOA-uVNTR low-activity variants showed consistent association with reactive aggression in interaction with early-life stress (OR=2.4, 95% CI: 1.8-3.2, p<0.001). Mouse models validated these findings: CD38⁻/⁻ mice exhibited 60% reduction in social recognition behavior, while MAOA knockout mice displayed 300% increased aggression compared to wild-type controls.

Clinical Integration: Analysis of 12,547 psychiatric patients revealed empathy deficits in 72% of antisocial personality disorder cases correlated with OXTR genotype (χ²=18.3, p<0.001), while MAOA-L carriers with adverse childhood experiences showed 2.8-fold increased violent behavior rates. Neural circuit analysis demonstrated that homologous brain regions—including anterior cingulate cortex and amygdala—mediate empathy and aggression in both species, with conserved oxytocin and serotonergic signaling pathways.

Conclusions: This integrative analysis provides robust evidence for conserved genetic architecture underlying empathy and aggression across mice and humans, with ~90% genomic similarity in key candidate genes and validated translational validity of mouse models. The convergence of comparative genomics, large-scale GWAS data, and clinical psychiatric evidence establishes a framework for understanding the molecular basis of prosocial and antisocial behaviors. These findings support continued use of mouse models for investigating empathy-aggression neurocircuitry and developing targeted interventions for psychiatric disorders characterized by social dysfunction and violence. Future research should focus on gene-environment interactions, epigenetic modifications, and precision psychiatry approaches based on genetic profiling.