Section on Neuropathology, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Biol Psychiatry. 2011 Jan 15;69(2):140-5. doi: 10.1016/j.biopsych.2010.10.032.
Human postmortem brain studies are critical for elucidating the pathophysiology and etiology of schizophrenia and other major mental illnesses. The traditional approach compares patients and control subjects but is potentially confounded by a number of artifacts, including medication, substance misuse, and other secondary effects of illness. Genetic advances now make possible a novel approach that focuses on how allelic variation in risk-associated genes affects expression and function of transcripts and proteins. These questions can be addressed in normal brain, overcoming to some extent the confounding effects of studying brains from subjects with schizophrenia; equally, extension of the studies to include cases also has advantages. Conceptually, the approach may be seen as the neuropathologic counterpart of genetic neuroimaging, representing a potentially powerful intermediate phenotype. For several schizophrenia susceptibility genes, the data show that risk-associated polymorphisms do affect gene expression or the function of the encoded protein; in some instances, expression of downstream or interacting partners of the gene are also altered. A further striking finding is that the implicated transcripts often appear to be enriched in, or specific to, human brain. Some also show enhanced expression in fetal brain. These considerations give unique importance to postmortem human brain tissue in elucidating the genetic mechanisms underlying schizophrenia and probably other neurodevelopmental disorders as well. Studies of this kind can provide clues as to the biological mechanisms of genetic association, especially when carried out in conjunction with experimental studies. Moreover, the data, interpreted judiciously, can strengthen the plausibility of the association itself.
人类死后大脑研究对于阐明精神分裂症和其他主要精神疾病的病理生理学和病因学至关重要。传统的方法是比较患者和对照者，但可能会受到许多因素的干扰，包括药物、物质滥用和疾病的其他次要影响。遗传进展现在使得一种新的方法成为可能，这种方法侧重于风险相关基因的等位基因变异如何影响转录物和蛋白质的表达和功能。这些问题可以在正常大脑中得到解决，在一定程度上克服了研究精神分裂症患者大脑的混杂效应；同样，将研究扩展到包括病例也有优势。从概念上讲，这种方法可以被视为遗传神经影像学的神经病理学对应物，代表了一种潜在的强大中间表型。对于几个精神分裂症易感性基因，数据表明，风险相关的多态性确实会影响基因表达或编码蛋白的功能；在某些情况下，该基因的下游或相互作用伙伴的表达也会改变。另一个引人注目的发现是，所涉及的转录本似乎在人类大脑中丰富或特异性表达。一些也显示在胎脑中表达增强。这些考虑因素使死后人类脑组织在阐明精神分裂症和可能其他神经发育障碍的遗传机制方面具有独特的重要性。这种类型的研究可以为遗传关联的生物学机制提供线索，尤其是当与实验研究结合进行时。此外，数据经过明智的解释，可以增强关联本身的合理性。
