Regulatory genomic profiling in schizophrenia

精神分裂症是一种严重的精神障碍，其特征是精神病症状、妄想和幻觉、精神紊乱、情感反应功能失调和认知功能改变。精神分裂症的社会和经济后果是严重的，使许多其他疾病黯然失色。精神分裂症的终生患病率约为1%，是全球疾病负担的重要组成部分，在世界发达国家中位列致残的十大原因之一。虽然精神分裂症的症状通常在青春期晚期或成年早期才出现，但神经影像学、神经病理学和流行病学研究的证据表明，精神分裂症是一种神经发育障碍，受产前大脑发育过程中影响的风险因素的影响。然而，到目前为止，这种疾病背后的神经生物学机制仍未明确，神经发育障碍与精神分裂症之间的分子证据也很有限。对精神分裂症病因的研究主要集中在描述这种疾病的遗传因素上。最近的精神分裂症全基因组关联研究（GWAS）非常成功，确定了100多个与风险相关的基因组区域。然而，尽管取得了这一成功，关于精神分裂症的具体致病基因，以及它们的功能在发育和疾病中是如何调节的，仍然存在不确定性。然而，基因组测序只是我们了解基因如何表达和调控的第一步。位于DNA序列之上的是第二层信息（“表观基因组”），它调节基因在何时何地被功能性转录。这些机制在确定人类大脑中特定细胞类型的基因转录模式中起着关键作用。这项研究的目的是，首次系统地检查这些调节基因组过程在精神分裂症中的作用。我们将从一组独特的死后脑样本中纯化神经元核，目的是确定与该疾病有关的新途径。鉴于精神分裂症的神经发育成分的证据，我们还将注释人类皮层发育过程中的基因调控模式，使我们能够探索疾病相关基因座在这一关键时期受到动态调控的假设。基于我们之前mrc资助的研究的新发现，我们的整合基因组学方法将汇集世界一流的研究人员和合作者，探索人类大脑发育过程中基因功能的动态调控及其与精神分裂症病因的相关性。

Schizophrenia is a severe psychiatric disorder, characterised by psychotic symptoms, delusions and hallucinations, disorganisation, dysfunctional affective responses, and altered cognitive functioning. The social and economic consequences of schizophrenia are severe, eclipsing those of many other illnesses. With a lifetime prevalence rate of ~1%, schizophrenia contributes significantly to the global burden of disease, ranking among the top ten causes of disability in developed countries worldwide. Although the symptoms of schizophrenia do not typically appear until late adolescence or early adulthood, evidence from neuroimaging, neuropathology and epidemiological studies indicate that it is a neurodevelopmental disorder, influenced by risk factors with effects during prenatal development of the brain. To date, however, the neurobiological mechanisms underlying the disorder remain largely undefined, and molecular evidence linking neurodevelopmental dysfunction to schizophrenia is limited. Studies into the causes of schizophrenia have focused on describing the genetic contribution to the disorder. Recent genome-wide association studies (GWAS) of schizophrenia have been highly successful, identifying over 100 regions of the genome associated with risk. Despite this success, however, there remains uncertainty about the specific causal genes involved in schizophrenia, and how their function is regulated in development and disease. Sequencing the genome was, however, only the first step in our quest to understand how genes are expressed and regulated. Sitting above the DNA sequence is a second layer of information (the 'epigenome') that mediates the regulation of when and where genes are functionally transcribed. These mechanisms play a critical role in determining cell-type-specific patterns of gene transcription in the human brain.This study aims, for the first time, to systematically examine the role of these regulatory genomic processes in schizophrenia. We will purify neuronal nuclei from a unique collection of post-mortem brain samples with the goal of identifying novel pathways involved in the disease. Given evidence for a neurodevelopmental component to schizophrenia, we will also annotate patterns of gene regulation across development of the human cortex, enabling us to explore the hypothesis that disease-associated loci are dynamically regulated during this critical period. Building on novel findings from our previous MRC-funded research, our integrated-genomics approach will bring together a world-class group of investigators and collaborators to explore the dynamic regulation of gene function during human brain development and its relevance to the aetiology of schizophrenia.