Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
National Institute on Drug Dependence, Peking University, Beijing, China.
Addiction. 2022 Sep;117(9):2515-2529. doi: 10.1111/add.15908. Epub 2022 May 10.
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.
Systemic literature search for genome-wide association (GWAS) and RNA-seq studies of alcohol/nicotine/drug use behavior (partially meets or not reported diagnostic criteria) and alcohol use behavior and disorder (AUBD), nicotine use behavior and disorder (NUBD) and drug use behavior and disorder (DUBD) was performed using PubMed and the GWAS catalog. Drug use was focused upon cannabis, opioid, cocaine and 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 ) 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.
Total SUBD-related 2910 genes were extracted from 75 GWAS studies (2 773 889 participants) and 17 RNA-seq studies. By overlapping the genes and pathways of AUBD, NUBD and DUBD, four shared genes (CACNB2, GRIN2B, PLXDC2 and PKNOX2), four shared pathways [two Gene Ontology (GO) terms of 'modulation of chemical synaptic transmission', 'regulation of trans-synaptic signaling', two Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of 'dopaminergic synapse', 'cocaine addiction'] were identified (significantly higher than random, P < 1 × 10 ). The top shared KEGG pathways (Benjamini-Hochberg-corrected P-value < 0.05) in the pairwise comparison of AUBD versus DUBD, NUBD versus DUBD, AUBD versus 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 were unique for NUBD.
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.
基因组和转录组研究极大地扩展了关于物质使用的生物学知识。然而，物质使用的全基因组研究结果缺乏系统的一致性和比较证据。在这里，我们结合了物质使用行为和障碍（SUBD）的所有全基因组研究结果，确定了不同 SUBD 的共同和独特的遗传因素。
使用 PubMed 和 GWAS 目录对酒精/尼古丁/药物使用行为（部分符合或未报告诊断标准）和酒精使用行为和障碍（AUBD）、尼古丁使用行为和障碍（NUBD）和药物使用行为和障碍（DUBD）的全基因组关联（GWAS）和 RNA-seq 研究进行了系统的文献搜索。药物使用集中在大麻、阿片类药物、可卡因和甲基苯丙胺上。GWAS 研究需要病例对照或病例/队列样本。RNA-seq 研究基于脑组织。从 GWAS 研究中提取包含显著单核苷酸多态性（P≤1×10）并在 RNA-seq 研究中报告为显著的基因。通过使用 Metascape 进行途径富集。通过使用蛋白质相互作用网络分析数据库识别基因相互作用网络。
从 75 项 GWAS 研究（2773889 名参与者）和 17 项 RNA-seq 研究中提取了总计 2910 个与 SUBD 相关的基因。通过重叠 AUBD、NUBD 和 DUBD 的基因和途径，确定了四个共同的基因（CACNB2、GRIN2B、PLXDC2 和 PKNOX2）、四个共同的途径[两个基因本体论（GO）术语“化学突触传递的调节”、“跨突触信号转导的调节”，两个京都基因与基因组百科全书（KEGG）途径“多巴胺能突触”、“可卡因成瘾”]（显著高于随机，P<1×10）。在 AUBD 与 DUBD、NUBD 与 DUBD、AUBD 与 NUBD 的两两比较中，KEGG 途径的 top 共享（Benjamini-Hochberg 校正 P 值<0.05）分别为“爱泼斯坦-巴尔病毒感染”、“内质网蛋白加工”和“神经活性配体-受体相互作用”。我们还确定了特定物质的遗传因素：即 ADH1B 和 ALDH2 是 AUBD 的独特基因，而 CHRNA3 和 CHRNA4 是 NUBD 的独特基因。
本系统综述确定了酒精、尼古丁和药物使用行为和障碍在全基因组水平上的共同和独特的基因和途径，并强调了物质使用行为和障碍的共同和独特易感性的关键生物学过程。
