Genomic heat maps were created using the Next-Generation Clustered Heatmaps interactive tool (Broom et al., 2017) https://build.ngchm.net/NGCHM-web-builder/View_HeatMap.html?adv=Y. The Reactome Knowledgebase (Fabregat et al., 2018) was used to identify and visualize the significantly affected biological domains and pathways (p<0.05). The PANTHER classification system (Mi et al., 2019) was used to identify significantly enriched (FDR < 0.05) GO terms by the ORT and the statistical enrichment test based on the Mann–Whitney U-test (Wilcoxon Rank-Sum test). The SynGO knowledgebase for the synapse (Koopmans et al., 2019) was used to determine the enrichment (FDR < 0.05) and to identify, annotate, and analyze the structural locations and functions of the significantly differentially expressed synaptic genes. As a background reference list, we used a list of genes expressed in the brain. This brain-expressed gene list contains 16,036 genes and is defined as ‘expressed in any GTEx v7 brain tissue’. This list was generated by ranking gene-expression levels in the brain versus other tissues (Ganna et al., 2016) using Genotype-Tissue Expression Consortia (GTEx) data (Lonsdale et al., 2013), and was kindly provided by Dr. Frank Koopmans (VU University and UMC Amsterdam). gProfiler (Raudvere et al., 2019) was used to identify the GO terms and pathways that were significantly enriched (FDR < 0.05) for the cell death processes and for the up- or downregulated pleiotropic immune-neural-synaptic DEGs.

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