The method S-PrediXcan (version 0.6.2)92 tested the association of EXT with gene expression in brain tissues. We used pre-computed tissue weights from the Genotype-Tissue Expression (GTEx, version 8.0) database as the reference dataset88. As inputs, we used the EXT summary statistics, LD matrices of the SNPs (available at the PredictDB Data Repository, http://predictdb.org, no version number), and transcriptome-tissue data related to 13 brain tissues: anterior cingulate cortex, amygdala, caudate basal ganglia, cerebellar hemisphere, cerebellum, cortex, frontal cortex, hippocampus, hypothalamus, nucleus accumbens basal ganglia, putamen basal ganglia, spinal cord and substantia nigra. We evaluated transcriptome-wide significance at the two-sided P < 2.77×10−7, which is Bonferroni-corrected adjusted for 13 tissues times 13,876 tested genes (180,388 gene-tissue pairs) (Supplementary Table 21). In Supplementary Table 22 we summarize the gene findings. Finally, we followed-up on the subset of gene findings that were consistently implicated in all gene-based methods, by generating an “externalizing gene network” as a parsimonious composite network (PCNet) and an “externalizing systems map” with Cytoscape (version 3.8.2)93,94, and applied Tissue Specific Expression Analysis (TSEA, version 1.0) and Specific Expression Analysis (SEA, version 1.1) to explore tissue and brain region specificity (Supplementary Tables 23–26).
