MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Maindy Road, Cardiff CF24 4HQ, UK.
University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
Hum Mol Genet. 2022 Sep 10;31(18):3095-3106. doi: 10.1093/hmg/ddac105.
Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A LOF may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.
大规模的精神分裂症基因组研究表明，组蛋白甲基化转录的表观遗传调控基因和突触组成成分的基因与精神疾病的风险有关。然而，这些途径在赋予精神疾病风险方面的相互作用尚不清楚。组蛋白甲基转移酶编码基因 SETD1A 的功能丧失（LoF）突变赋予精神分裂症的风险很大。SETD1A 被认为参与神经元回路的发育和功能，具有多种作用。在这里，我们采用多组学方法研究了从胚胎第 14 天到出生后第 70 天的五个发育时间点，杂合性 Setd1a LoF 对小鼠皮层基因表达和突触组成的影响。使用 RNA 测序，我们观察到 Setd1a LoF 导致富含线粒体途径的基因持续下调。这种影响扩展到突触体，在突触体中，我们发现线粒体和突触蛋白都具有年龄特异性的破坏。利用大规模的患者基因组学数据，我们没有发现与差异表达转录本或蛋白质中精神分裂症遗传关联的富集，这表明它们来自与基因组研究中所涉及的风险机制不同的机制。本研究强调了 SETD1A LOF 可能导致精神分裂症风险的生物学途径。需要进一步的工作来确定在该模型中观察到的效应是否反映了人类病理学。
