Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10021, USA.
Lieber Institute for Brain Development and the Departments of Psychiatry, Neurology, Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nat Rev Neurosci. 2017 Dec;18(12):727-740. doi: 10.1038/nrn.2017.125. Epub 2017 Oct 26.
Schizophrenia is a severe neuropsychiatric disorder with a longstanding history of neurobiological investigation. Although the underlying causal mechanisms remain unknown, early neurodevelopmental events have been implicated in pathogenesis, initially by epidemiological and circumstantial data but more recently by brain-specific molecular and genetic findings. Notably, genomic research has recently uncovered discrete risk variants and risk loci associated with schizophrenia, with the potential to elucidate disease mechanisms. This Review revisits the neurodevelopmental model of schizophrenia from a current genetics perspective, delineating the complex genetic basis of the disorder and highlighting gene expression and epigenetic analyses of post-mortem cortical tissue that suggest that early brain development mediates genetic risk associated with schizophrenia. Future functional genomics investigations will accordingly need to characterize schizophrenia risk loci in relevant neurodevelopmental models.
精神分裂症是一种严重的神经精神疾病，其神经生物学研究历史悠久。尽管其根本病因机制尚不清楚，但早期神经发育事件已被牵涉到发病机制中，最初是通过流行病学和间接数据，最近则是通过大脑特异性分子和遗传学发现。值得注意的是，基因组研究最近发现了与精神分裂症相关的离散风险变异和风险位点，这有可能阐明疾病机制。本综述从当前遗传学的角度重新审视了精神分裂症的神经发育模型，阐述了该疾病复杂的遗传基础，并强调了死后皮质组织的基因表达和表观遗传分析，这些分析表明早期大脑发育介导了与精神分裂症相关的遗传风险。因此，未来的功能基因组学研究需要在相关的神经发育模型中对精神分裂症风险位点进行特征描述。
