A transcriptome-wide association analysis25 of the addiction-rf using multiple tissues simultaneously from GTEx in MetaXcan (See Methods) identified 35 genes in 13 brain regions (Figure 2; Supplemental Table 15). Gene-set analysis using FUMA23 revealed that these genes were enriched for gene sets and pathways related to neural cells and T-cell processes (Supplemental Figure 7; Supplemental Table 16). Transcriptome-wide analyses with PsychEncode data found 29 significantly associated genes and 11 genes that overlapped with those identified in the GTEx analysis (AMT, DALRD3, GPX1, KLHDC8B, NCKIPSD, NICN1, P4HTM, PPP6C, RHOA, SNX17, WDR6) (Figure 2). Linking transcriptome-wide patterns from our GTEx MetaXcan analysis to perturbagens that cross the blood-brain barrier from the Library of Integrated Network-Based Cellular Signatures (LINCS)26 database, identified 104 medications approved by the U. S. Food and Drug Administration that reverse the addiction-rf transcriptional profile (Supplemental Table 17). Medications currently used to treat SUDs (e.g., varenicline, smoking cessation), other psychiatric conditions (e.g., reboxetine, depression) as well as those used for other purposes (e.g., mifepristone, pregnancy termination; currently under clinical investigation for treating AUD; riluzole, amyotrophic lateral sclerosis) were identified.
