To evaluate the functional aspects of these genetic ancestry-associated DEGs (global and local ancestry), we performed gene set enrichment analysis (GSEA) for each brain region. Notably, while neuronal gene sets were not enriched, we observed significant enrichment (GSEA and hypergeometric testing, q < 0.05) for terms primarily related to the immune response, including innate, adaptive and virus responses (Supplementary Data 3, Fig. 2b and Supplementary Fig. 4). Interestingly, the caudate nucleus showed an opposite direction of effect compared with the dentate gyrus, DLPFC and hippocampus. Specifically, the caudate nucleus showed enrichment of the immune response associated with DEGs upregulated in the AA proportion, while the dentate gyrus, DLPFC and hippocampus showed enrichment for immune-related pathways associated with DEGs upregulated in the EA proportion (Fig. 2b and Supplementary Fig. 5). While not significant, we observed the same pattern of opposite directionality of effect for immune-related pathways with local ancestry-associated DEGs (Supplementary Fig. 6). The binary combined analysis (BAs and WAs) also revealed similar immune response enrichment with directionality dependent on brain region (Supplementary Note).
