Genome‐wide association studies have identified multiple genetic risk factors underlying susceptibility to substance use, however, the functional genes and biological mechanisms remain poorly understood. The discovery and characterization of risk genes can be facilitated by the integration of genome‐wide association data and gene expression data across biologically relevant tissues and/or cell types to identify genes whose expression is altered by DNA sequence variation (expression quantitative trait loci; eQTLs). The integration of gene expression data can be extended to the study of genetic co‐expression, under the biologically valid assumption that genes form co‐expression networks to influence the manifestation of a disease or trait. Here, we integrate genome‐wide association data with gene expression data from 13 brain tissues to identify candidate risk genes for 8 substance use phenotypes. We then test for the enrichment of candidate risk genes within tissue‐specific gene co‐expression networks to identify modules (or groups) of functionally related genes whose dysregulation is associated with variation in substance use. We identified eight gene modules in brain that were enriched with gene‐based association signals for substance use phenotypes. For example, a single module of 40 co‐expressed genes was enriched with gene‐based associations for drinks per week and biological pathways involved in GABA synthesis, release, reuptake and degradation. Our study demonstrates the utility of eQTL and gene co‐expression analysis to uncover novel biological mechanisms for substance use traits.

中文翻译：

---

基于综合系统的物质使用分析：基于 eQTL 的基因检测、基因网络和生物学机制

全基因组关联研究已经确定了导致物质使用易感性的多种遗传风险因素，但是，功能基因和生物学机制仍然知之甚少。通过整合跨生物相关组织和/或细胞类型的全基因组关联数据和基因表达数据，可以促进风险基因的发现和表征，以识别其表达因 DNA 序列变异而改变的基因（表达数量性状位点；eQTLs ）。基因表达数据的整合可以扩展到遗传共表达的研究，在生物学上有效的假设下，基因形成共表达网络来影响疾病或性状的表现。这里，我们将全基因组关联数据与来自 13 个脑组织的基因表达数据相结合，以确定 8 种物质使用表型的候选风险基因。然后，我们测试组织特异性基因共表达网络中候选风险基因的富集，以确定功能相关基因的模块（或组），其失调与物质使用的变化有关。我们确定了大脑中的八个基因模块，这些模块富含用于物质使用表型的基于基因的关联信号。例如，一个包含 40 个共表达基因的单一模块富含每周饮料的基因关联以及参与 GABA 合成、释放、再摄取和降解的生物途径。