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

Jiayang Gao; Xin Guo; Chunxia Yan; Xiaojuan Gong; Pan Ma; Shanzhi Gu; Bao Zhang

doi:10.1016/j.gene.2022.147048

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

Gene. 2023 Jan 30:851:147048. doi: 10.1016/j.gene.2022.147048. Epub 2022 Nov 13.

Authors

Jiayang Gao¹, Xin Guo², Chunxia Yan¹, Xiaojuan Gong¹, Pan Ma¹, Shanzhi Gu³, Bao Zhang⁴

Affiliations

¹ College of Medicine & Forensic, Health Science Center, Xi'an Jiao Tong University, Xi'an, Shaanxi, China.
² State Key Laboratory for Strength and Vibration of Structures, School of Aerospace Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
³ College of Medicine & Forensic, Health Science Center, Xi'an Jiao Tong University, Xi'an, Shaanxi, China. Electronic address: gushanzhi@mail.xjtu.edu.cn.
⁴ College of Medicine & Forensic, Health Science Center, Xi'an Jiao Tong University, Xi'an, Shaanxi, China. Electronic address: zhangbao_814@mail.xjtu.edu.cn.

PMID: 36379386
DOI: 10.1016/j.gene.2022.147048

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.

Keywords: Cannabis use disorder (CUD); Causal genes; Pathway enrichment analysis; Transcriptome-wide association study (TWAS).

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Gene Expression Profiling
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Marijuana Abuse* / genetics
Polymorphism, Single Nucleotide
RNA, Messenger / genetics
Transcriptome*

Substances

RNA, Messenger
SH2B1 protein, human
Adaptor Proteins, Signal Transducing