Large numbers of genetic loci have been identified that are known to contain common risk alleles for schizophrenia, but linking associated alleles to specific risk genes remains challenging. Given that most alleles that influence liability to schizophrenia are thought to do so by altered gene expression, intuitively, case–control differential gene expression studies should highlight genes with a higher probability of being associated with schizophrenia and could help identify the most likely causal genes within associated loci. Here, we test this hypothesis by comparing transcriptome analysis of the dorsolateral prefrontal cortex from 563 schizophrenia cases and 802 controls with genome-wide association study (GWAS) data from the third wave study of the Psychiatric Genomics Consortium. Genes differentially expressed in schizophrenia were not enriched for common allelic association statistics compared with other brain-expressed genes, nor were they enriched for genes within associated loci previously reported to be prioritized by genetic fine-mapping. Genes prioritized by Summary-based Mendelian Randomization were underexpressed in cases compared to other genes in the same GWAS loci. However, the overall strength and direction of expression change predicted by SMR were not related to that observed in the differential expression data. Overall, this study does not support the hypothesis that genes identified as differentially expressed from RNA sequencing of bulk brain tissue are enriched for those that show evidence for genetic associations. Such data have limited utility for prioritizing genes in currently associated loci in schizophrenia.

中文翻译：

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精神分裂症脑组织病例对照差异基因表达与遗传关联之间的关系

已鉴定出大量已知含有精神分​​裂症常见风险等位基因的基因位点，但将相关等位基因与特定风险基因联系起来仍然具有挑战性。鉴于大多数影响精神分裂症的等位基因被认为是通过改变基因表达来实现的，直观地讲，病例对照差异基因表达研究应该突出与精神分裂症相关的可能性较高的基因，并有助于识别其中最可能的致病基因。相关基因座。在这里，我们通过将 563 名精神分裂症病例和 802 名对照者的背外侧前额叶皮层的转录组分析与精神病基因组学联盟第三波研究的全基因组关联研究 (GWAS) 数据进行比较来检验这一假设。与其他脑表达基因相比，精神分裂症中差异表达的基因并未富集常见等位基因关联统计数据，也没有富集先前报道的通过遗传精细作图优先考虑的相关位点内的基因。与相同 GWAS 位点中的其他基因相比，基于摘要的孟德尔随机化优先排序的基因在病例中表达不足。然而，SMR预测的表达变化的总体强度和方向与差异表达数据中观察到的结果无关。总体而言，这项研究并不支持以下假设：通过大量脑组织的 RNA 测序鉴定出差异表达的基因，对于那些显示出遗传关联证据的基因来说是富集的。这些数据对于对当前精神分裂症相关基因座中的基因进行优先排序的效用有限。