Transcriptome-wide association study by different approaches reveals candidate causal genes for cannabis use disorder

Abstract

Cannabis is one of the most commonly used psychoactive substances, which could induce moderate-severe cannabis use disorders (CUD). Here, a tissue-specific transcriptome-wide association study (TWAS) of CUD was performed by FUSION and S-PrediXcan, utilizing a genome-wide association study (GWAS) dataset of CUD (including 43,380 cases and 141,385 controls of European ancestry) and gene expression reference data from 17 different brain-related and non-brain related tissues, with totally 26 TWAS-associated genes were identified, including CADM2 (P = 2.13 × 10-17), SRR (P = 8.09 × 10-9) and TUFM (P = 1.24 × 10-8). Fine-mapping of causal gene sets (FOCUS) was used to prioritize genes with strong evidence for causality, and SRR, CADM2-AS1, and SH2B1 were prioritized with a posterior probability of 0.973, 0.951, and 0.788, respectively. Furthermore, gene ontology (GO) and pathway enrichment analysis on CUD-associated genes were performed, including cytosol, protein binding, nucleoplasm, metabolic pathways, and herpes simplex virus 1 infection. These findings could provide new insights for understanding the mechanism of CUD.