Variants identified by genome-wide association studies (GWAS) are often expression quantitative trait loci (eQTLs), suggesting they are proxies or are themselves regulatory. Across many data sets, analyses show that variants often affect multiple genes. Lacking data on many tissue types, developmental time points, and homogeneous cell types, the extent of this one-to-many relationship is underestimated. This raises questions on whether a disease eQTL target gene explains the genetic association or is a bystander and puts into question the direction of expression effect of on the risk, since the many variants-regulated genes may have opposing effects, imperfectly balancing each other. We used two brain gene expression data sets (CommonMind and BrainSeq) for mediation analysis of schizophrenia-associated variants. We confirm that eQTL target genes often mediate risk but the direction in which expression affects risk is often different from that in which the risk allele changes expression. Of 38 mediator genes significant in both data sets 33 showed consistent mediation direction (Chi² test p = 6 × 10⁻⁶). One might expect that the expression would correlate with the risk allele in the same direction it correlates with the disease. For 15 of these 33 (45%), however, the expression change associated with the risk allele was protective, suggesting the likely presence of other target genes with overriding effects. Our results identify specific risk mediating genes and suggest caution in interpreting the biological consequences of targeted modifications of gene expression, as not all eQTL targets may be relevant to disease while those that are, might have different from expected directions.

中文翻译：

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精神分裂症风险等位基因通常影响许多基因的表达，每个基因可能对风险有不同的影响：中介分析

全基因组关联研究 (GWAS) 鉴定的变异通常是表达数量性状位点 (eQTL)，表明它们是代理或本身具有调节作用。在许多数据集中，分析表明变异通常会影响多个基因。由于缺乏许多组织类型、发育时间点和同质细胞类型的数据，这种一对多关系的程度被低估了。这就提出了疾病 eQTL 靶基因是否解释了遗传关联还是旁观者的问题，并对风险的表达效应方向提出了质疑，因为许多变异调控基因可能具有相反的作用，彼此不完美平衡。我们使用两个大脑基因表达数据集（CommonMind 和 BrainSeq）对精神分裂症相关变异进行中介分析。我们证实，eQTL 靶基因通常介导风险，但表达影响风险的方向通常与风险等位基因改变表达的方向不同。在两个数据集中均显着的 38 个介导基因中，有 33 个显示出一致的介导方向（Chi²检验p  = 6 × 10 ⁻⁶ )。人们可能期望该表达与风险等位基因的相关性与与疾病相关的方向相同。然而，对于这 33 个基因中的 15 个（45%）来说，与风险等位基因相关的表达变化是保护性的，这表明可能存在具有压倒性作用的其他目标基因。我们的结果确定了特定的风险介导基因，并建议谨慎解释基因表达靶向修饰的生物学后果，因为并非所有 eQTL 目标都可能与疾病相关，而那些与疾病相关的 eQTL 目标可能与预期方向不同。