Expression patterns of risk genes associated with three evolutionarily relevant syndromes in rhesus macaque and human brains

Depressive disorder (DD), Alzheimer’s disease (AD), and schizophrenia (SZ) are evolutionarily relevant traits that disrupt neural networks supporting affect and cognition. While genome-wide association studies have identified risk-related genes for these diseases, how the expression of these genes compare across species remains unclear. In this study, we examined the spatial and temporal expression of ~2,000 disease-associated genes in human and rhesus macaque brains. Distinct cross-species signatures emerged. DD-linked genes showed broad cortical and subcortical expression in humans but were confined to postnatal subcortical regions in macaques. The divergent subset was enriched for neuron differentiation, migration, synaptic signalling, and cognition. SZ-linked genes were localised to prenatal ganglionic eminences in macaques but extended to cortical, subcortical, and cerebellar structures in humans. AD-linked genes showed postnatal cortical-hippocampal macaque expression, and broader cortical-subcortical human expression. Cross-species spatial comparisons revealed a significant negative correlation for DD genes, suggesting an expansion of DD-related circuitry from conserved affective hubs in macaques to distributed emotion-cognition networks in humans. SZ genes exhibited a similar, though non-significant, negative trend, while AD genes showed a weak, non-significant correlation, indicating an absence of systematic expression shifts. Together, these results highlight how evolutionary shifts in gene expression, such as in DD circuitry, may have shaped emotional and cognitive functions in humans, and prompt future studies on susceptibility to psychiatric and neurodegenerative disorders.