Methylomic profiling in schizophrenia: towards an integrated genetic-epigenetic approach

精神分裂症是一种严重的精神障碍，以精神病症状、妄想和幻觉、组织紊乱、情感反应障碍和认知功能改变为特征。精神分裂症的社会和经济后果是严重的，超过了许多其他疾病。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，在全球发达国家中排名前十位的残疾原因之一。目前理解精神分裂症病因的方法主要集中在揭示精神分裂症的遗传因素，尽管识别风险变异并不简单。此外，各研究之间存在相当大的异质性，遗传风险变异作用背后的机制在很大程度上仍不清楚。因此，尽管进行了大量的研究工作，我们仍然没有更深入地了解SZ的确切病因，距离实现新的诊断和治疗策略的后基因组承诺还有很长的路要走。然而，基因组测序只是我们探索了解基因是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”)，它调节基因何时何地被功能性转录。与稳定且高度保守的DNA序列不同，表观遗传过程可以是高度动态的：它们不仅受发育调节，而且还可以通过暴露于一系列外部环境因素和细胞中的随机事件来修改。这项研究的目的是首次系统地研究表观遗传过程在精神分裂症中的作用，重点是DNA甲基化，这是对DNA的一种化学修饰，可以直接影响基因转录和功能。我们将使用尖端方法在几个独特的样本集合中检查DNA甲基化的全基因组模式。首先，我们将使用大量精神分裂症患者和对照的协作性收集。这些样本已经在基因水平上进行了广泛的研究，使我们能够对精神分裂症采取综合的遗传-表观遗传学方法。其次，我们将检查基因相同的同卵双胞胎之间的表观遗传学差异，其中一个双胞胎患有精神分裂症，另一个没有。第三，我们将检查精神分裂症患者死后脑组织的差异。最后，我们将评估精神分裂症高危人群基因组特定区域的表观遗传学变化，跟踪DNA甲基化与疾病发病的变化。我们提出的整合遗传-表观遗传学的方法将一群世界级的表观遗传学家、遗传学家、临床医生和生物信息学家聚集在一起，最终目标是识别精神分裂症的外周表观遗传生物标记物，并改变对疾病的诊断、治疗和未来的病因学方法。

Schizophrenia is a severe psychiatric disorder, characterized 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. Current approaches to understanding the causes of schizophrenia have focused primarily on uncovering a genetic contribution to the disorder, although identifying risk variants has not been straightforward. Furthermore, there is considerable heterogeneity across studies and the mechanism behind the action of genetic risk variants remains largely unknown. Despite considerable research effort, therefore, we are remain no closer to understanding the precise aetiology of SZ and a long way from realising the post-genomic promises of novel diagnostic and therapeutic strategies. 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. Unlike the DNA sequence, which is stable and strongly conserved, epigenetic processes can be highly dynamic: not only are they developmentally-regulated, but they can also be modified by exposure to a range of external environmental factors and stochastic events in the cell. This study aims, for the first time, to systematically examine the role of epigenetic processes in schizophrenia, focusing on DNA methylation, a chemical modification to DNA that can directly influence gene transcription and function. We will use cutting-edge methods to examine genome-wide patterns of DNA methylation in several unique collections of samples. First, we will use a large collaborative collection of schizophrenia patients and controls. These samples have already been extensively studied at the genetic level, enabling us to undertake an integrated genetic-epigenetic approach to schizophrenia. Second, we will examine epigenetic differences within genetically-identical monozygotic twin-pairs, where one twin has schizophrenia and the other does not. Third, we will examine differences in brain tissue taken post-mortem from patients with schizophrenia. Finally, we will assess epigenetic changes across specific regions of the genome in individuals at high-risk for developing schizophrenia, tracking changes in DNA methylation with disease onset. Our proposed integrated genetic-epigenetic approach brings together a world-class group of epigeneticists, geneticists, clinicians and bioinformaticians with the ultimate goal of identifying peripheral epigenetic biomarkers for schizophrenia and transforming diagnostic, therapeutic, and future aetiological approaches to the disease.