Although the MHC region did not appear to drive our immune enrichment, immune variation, either from HLA gene diversity or glial cell composition, could still contribute to our observed transcriptional changes. We next assessed the contributions of HLA variation or glial cell composition to these expression changes. Adding glial cell composition (astrocytes, microglia, macrophages, oligodendrocytes, oligodendrocyte progenitor cells (OPCs) and T cells) as covariates in our differential expression model showed a minimal effect, as evidenced by a high degree of correlation of effect sizes with the original model (Spearman rho from 0.81 to 0.92; Supplementary Fig. 21a). For HLA variation, we added the first five principal components of imputed HLA alleles (explaining 66% of the variance) as covariates, which similarly showed minimal change in effect sizes (Spearman rho from 0.83 to 0.87; Supplementary Fig. 21b). These sensitivity analyses collectively suggest that immune variation contributes only minimally to transcriptional changes for global ancestry-associated DEGs.
