Addiction. 2022 May 2. doi: 10.1111/add.15908. Online ahead of print.
BACKGROUND AND AIMS: Genomic and transcriptomic findings greatly broaden the biological knowledge regarding substance use. However, systematic convergence and comparison evidence of genome-wide findings is lacking for substance use. Here, we combined all the genome-wide findings from both substance use behavior and disorder (SUBD) and identified common and distinguishing genetic factors for different SUBDs.
METHODS: Systemic literature search for genome-wide association (GWAS) and RNA-seq studies of alcohol/nicotine/drug use behavior (partially meets or no-reported diagnostic criteria) and disorder (AUBD, NUBD, DUBD) was performed using PubMed and GWAS Catalog. Drug use was focused on cannabis, opioid, cocaine, methamphetamine use. GWAS studies required case-control or case/cohort samples. RNA-seq studies were based on brain tissues. The genes which contained significant single nucleotide polymorphism (p≤1×10-6 ) in GWAS and reported as significant in RNA-seq studies were extracted. Pathway enrichment was performed by using Metascape. Gene interaction networks were identified by using the Protein Interaction Network Analysis database.
RESULTS: Total SUBD-related 2910 genes were extracted from 75 GWAS studies (2,773,889 participants) and 17 RNA-seq studies. By overlapped the genes and pathways of AUBD, NUBD, and DUBD, 4 shared genes (CACNB2, GRIN2B, PLXDC2, and PKNOX2), 4 shared pathways (2 GO terms of ‘modulation of chemical synaptic transmission’, ‘regulation of trans-synaptic signaling’, 2 KEGG pathways of ‘Dopaminergic synapse’, ‘Cocaine addiction’) were identified (significantly higher than random, p<1×10-5 ). The top shared KEGG pathways (B-H corrected p-value<0.05) in the pairwise comparison of AUBD vs. DUBD, NUBD vs. DUBD, AUBD vs. NUBD were « Epstein-Barr virus infection », « protein processing in endoplasmic reticulum », and « neuroactive ligand-receptor interaction » respectively. We also identified substance-specific genetic factors: i.e., ADH1B and ALDH2 were unique for AUBD, while CHRNA3 and CHRNA4 for NUBD.
CONCLUSIONS: This systematic review identifies the shared and unique genes and pathways for alcohol, nicotine, and drug use behaviors and disorders at the genome-wide level and highlights critical biological processes for the common and distinguishing vulnerability of substance use behaviors and disorders.
Source: ncbi 2