Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York City, NY 10029, USA.
J Hum Genet. 2010 May;55(5):285-92. doi: 10.1038/jhg.2010.24. Epub 2010 Mar 26.
Schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia.
精神分裂症是一种高度复杂的遗传性疾病，其特征是存在许多遗传易感性因素，每个因素都使患病风险略有增加。尽管许多连锁或关联研究已经确定了一大组与精神分裂症相关的基因座，但其中许多存在争议。此外，这些基因座中只有一小部分与已在精神分裂症中显示表达变化的大量累积基因池重叠。在这里，我们应用基因组基因功能方法来鉴定直接影响基因表达的易感性基因座，从而导致精神分裂症中的功能异常。我们使用生物信息学工具，对基于文献的易感性基因座与我们之前微阵列研究中获得的与精神分裂症相关的表达基因列表进行综合分析（《人类遗传学杂志》（2009 年）54：665-75），随后使用 qPCR 确认基因表达变化。我们发现九个基因（CHGB、SLC18A2、SLC25A27、ESD、C4A/C4B、TCP1、CHL1 和 CTNNA2）显示出涉及突触和神经传递、能量代谢和防御机制以及分子伴侣和细胞骨架的基因功能相关性。我们的研究结果进一步支持了这些基因在遗传影响和功能后果方面在精神分裂症发展中的作用。有趣的是，这九个基因中有四个位于 6 号染色体上，这表明精神分裂症存在特殊的染色体脆弱性。
