MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
University of Exeter Medical School, University of Exeter, Exeter, UK.
Am J Med Genet B Neuropsychiatr Genet. 2023 Jul-Sep;192(5-6):85-92. doi: 10.1002/ajmg.b.32931. Epub 2023 Jan 18.
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.
大量的遗传基因座已被确定，已知这些基因座包含精神分裂症的常见风险等位基因，但将相关等位基因与特定的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易感性的等位基因被认为是通过改变基因表达来实现的，直观地说，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更高的基因，并有助于确定相关基因座内最有可能的因果基因。在这里，我们通过比较来自精神分裂症病例 563 例和对照 802 例的背外侧前额叶皮层的转录组分析，以及第三波精神疾病基因组学联盟的全基因组关联研究 (GWAS) 数据，来检验这一假设。与其他在大脑中表达的基因相比，精神分裂症中差异表达的基因没有富集常见等位基因关联统计数据，也没有富集以前通过遗传精细映射优先报告的与相关基因座相关的基因。与其他在相同 GWAS 基因座中的基因相比，Summary-based Mendelian Randomization 优先的基因在病例中表达下调。然而，SMR 预测的表达变化的整体强度和方向与差异表达数据中观察到的无关。总的来说，这项研究不支持这样的假设，即从大脑组织的 RNA 测序中鉴定为差异表达的基因富集了那些表现出遗传关联证据的基因。此类数据对于优先考虑当前与精神分裂症相关基因座中的基因的用途有限。
