精神分裂症与多巴胺和5-羟色胺代谢通路的基因组合的关联研究
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摘要
精神分裂症是迄今为止人类所面临的最为常见和最为严重的精神疾患之一，发病机制迄今不明，在人群中的患病率约为1％。家系、双生子和寄养研究都显示遗传因素对于精神分裂症的发病起主要作用。它是一种复杂的多基因疾病，许多微效或中效基因的相互作用以及与环境因素的作用导致了疾病的发生。然而，对疾病易感基因的识别是相当困难的。
多巴胺和5-羟色胺是中枢神经系统两种重要的神经递质。许多研究显示精神分裂症病人多巴胺和5-羟色胺系统功能异常。此外，多巴胺和5-羟色胺神经传递能够在不同的解剖学水平上相互作用，并影响多巴胺功能的不同方面。因此，多巴胺和5-羟色胺代谢通路上的基因都应作为精神分裂症遗传学研究的对象，并且应该系统地研究它们对于该疾病易感性的相互作用和联合效应。
在本研究中，我们在北京地区收集了80例特征明显、同质性高的偏执型精神分裂症病人和108例严格匹配的正常对照，所有样本均为汉族且互不相关。我们从公共数据库中选择了50个参与多巴胺和5-羟色胺代谢的酶基因，并且在它们的编码区和非翻译区选取了167个已报道的单核苷酸多态性(SNP)，通过聚合酶链式反应和限制性片段长度多态性(PCR-RFLP)方法或PCR产物的直接测序法进行了基因分型。一共有35个基因的77个SNP在所研究的样本中显示有多态性，并且用于数据分析。由于传统的单位点关联分析方法忽视了精神分裂症的多基因本质，而且没有考虑易感基因之间的相互作用和联合效应，所以在本研究中，我们提出了用一个多位点基因型组合的最大后验概率(posterior probability)来衡量它致病的绝对风险。同时，我们运用了一个基于扰动(perturbation)和平均(average)的算法来降低干扰(noise)，
Schizophrenia is one of the most common, devastating, and least understood neuropsychiatric illnesses affecting about 1% of the world's population. Family, twin and adoption studies have shown the disorder to have a strong genetic component, but the mode of transmission is complex. A number of genes with small to moderate effects are involved in combination in the etiology of the disorder. However, the identification of disease susceptibility genes has been proven difficult.
Dopamine (DA) and serotonin (5-HT) are two of the most important neurotransmitters in the central nervous system. Several lines of evidence implicated the altered dopaminergic and serotonergic system in schizophrenia. Moreover, DA and 5-HT neurotransmission could interact at different anatomical levels, and affect different aspects of DA function. Therefore, genes of the enzymes involved in dopaminergic and serotonergic pathways are natural candidates for the genetic studies of schizophrenia, and should be
多巴胺和5-羟色胺是中枢神经系统两种重要的神经递质。许多研究显示精神分裂症病人多巴胺和5-羟色胺系统功能异常。此外，多巴胺和5-羟色胺神经传递能够在不同的解剖学水平上相互作用，并影响多巴胺功能的不同方面。因此，多巴胺和5-羟色胺代谢通路上的基因都应作为精神分裂症遗传学研究的对象，并且应该系统地研究它们对于该疾病易感性的相互作用和联合效应。
在本研究中，我们在北京地区收集了80例特征明显、同质性高的偏执型精神分裂症病人和108例严格匹配的正常对照，所有样本均为汉族且互不相关。我们从公共数据库中选择了50个参与多巴胺和5-羟色胺代谢的酶基因，并且在它们的编码区和非翻译区选取了167个已报道的单核苷酸多态性(SNP)，通过聚合酶链式反应和限制性片段长度多态性(PCR-RFLP)方法或PCR产物的直接测序法进行了基因分型。一共有35个基因的77个SNP在所研究的样本中显示有多态性，并且用于数据分析。由于传统的单位点关联分析方法忽视了精神分裂症的多基因本质，而且没有考虑易感基因之间的相互作用和联合效应，所以在本研究中，我们提出了用一个多位点基因型组合的最大后验概率(posterior probability)来衡量它致病的绝对风险。同时，我们运用了一个基于扰动(perturbation)和平均(average)的算法来降低干扰(noise)，
Schizophrenia is one of the most common, devastating, and least understood neuropsychiatric illnesses affecting about 1% of the world's population. Family, twin and adoption studies have shown the disorder to have a strong genetic component, but the mode of transmission is complex. A number of genes with small to moderate effects are involved in combination in the etiology of the disorder. However, the identification of disease susceptibility genes has been proven difficult.
Dopamine (DA) and serotonin (5-HT) are two of the most important neurotransmitters in the central nervous system. Several lines of evidence implicated the altered dopaminergic and serotonergic system in schizophrenia. Moreover, DA and 5-HT neurotransmission could interact at different anatomical levels, and affect different aspects of DA function. Therefore, genes of the enzymes involved in dopaminergic and serotonergic pathways are natural candidates for the genetic studies of schizophrenia, and should be
引文
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