精神分裂症中的多巴胺通路相关基因的多位点相互作用模式研究
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摘要
精神分裂症是一种常见的病因尚未完全阐明的精神疾病,人群终生患病率约为1%,多于青壮年发病,严重威胁人类的身心健康,并且给家庭和社会带来沉重负担。
多年来的研究表明,精神分裂症是一种典型的多基因复杂性状疾病,其中遗传因素所占的比重更大,遗传度可达80%,但是通过关联研究和连锁分析均未能找到确切的致病基因。这主要是因为精神分裂症临床分型复杂,症状多样,若将不同类型的患者混杂起来研究将难以对这种异质性疾病作出可信的结论;同时该病作为多基因病的一种,其发病是由许多微效基因共同作用决定的,若孤立地研究某个候选基因或候选染色体区域与疾病的关系,也难以得出满意的结果。这就需要在研究中,通过表型甚至内表型将样本纯化,并研究多个基因与疾病乃至表型的关系。另外,在本课题组前期工作中,以多巴胺代谢通路中涉及的基因为研究对象,发现位于儿茶酚胺氧位甲基转移酶(Catechol-O-methyltransferase,COMT)和乙醛脱氢酶(Aldehyde dehydrogenase 3B1,ALDH3B1)基因内含子区的两个单核苷酸多态性(Single Nucleotide Polymorphism,SNP)的联合作用,可以增高偏执型精神分裂症的易感性,同时也发现该通路中的基因与精神分裂症某些表型的发生相关。
综合精神分裂症的遗传学特点和课题组前期研究成果,本论文从两个方面对精神分裂症进行研究:1、进一步探索COMT和ALDH381基因的相互作用对偏执型精神分裂症发生的影响。2、以精神分裂症为切入点研究幻听表型的发生机制。
在第一部分工作中,我们在540例偏执型精神分裂症患者和660例对照中,筛查了两基因全部外显子中可能的功能SNPs,受试者均为中国北方汉族人群。对于筛查到的易感SNPs,检测其对于精神病性症状的影响,同时使用听觉odd-ball范式检测该易感SNPs对P300波幅和潜伏期的影响;使用Reai-time PCR的方法检测该易感SNPs对基因表达的影响。结果发现,只有在携带ALDH3B1 rs3751082-A等位基因的人群中,COMT rs4633-T等位基因与偏执型精神分裂症的易感性(P=0.004),幻觉的发生(P=5.141 E-5),患者(P=0.006)和对照(P=0.02)中P300潜伏期的延长,对照中COMT基因表达量的升高(P=0.002)显著相关;而在携带ALDH3B1 rs3751082 G/G基因型的人群中,却没有发现rs4633-T等位基因与以上各项指标的相关性。
在第二部分工作中,我们首先在96例具有和不具有幻听表型的精神分裂症患者和108例对照中,初步研究了多巴胺信号传导通路的27个基因的47个SNPs与幻听的关系。发现胆囊收缩素基因(cholycystokinin receptor A,CCKAR)rs1700908多态性在具有和不具有幻听表型的精神分裂症患者间分布具有显著差异(Adjust P=0.02)。为验证这一结果,在更大样本中对CCKAR基因进行了全面筛查。结果显示,CCKAR基因的rs1800857-rs2071011单倍型与幻听的发生相关(Adjust P=0.003)。
在第一部分工作中,我们不仅在遗传学水平上保证了结果的可重复性,而且在功能学水平上给予了多层面的证据支持,从而系统地阐释了COMT和ALDH3B1基因与精神分裂症的关系。在第二部分工作中,我们以幻听这一特异表型入手,严格控制样本分层,并且通过两阶段式病例-对照研究,和对阳性结果基因的全面筛查,证实了CCKAR基因与幻听表型的相关性,为精神分裂症的研究提供了新的思路。
Schizophrenia is a common yet severe psychiatric condition that affects about 1%of the population.The disorder always suffers the youth,and brings heavy economical and social burdens to families and societies.
After decades of study,schizophrenia is considered as a typical complex disorder. Although the genetic factors account for much of the etiology and the heredity of schizophrenia is over 80%,the candidate gene is still unknown after amounts of association and linkage studies.These studies are mainly complicated by complex genetic background and clinical heterogeneity.Schizophrenia is unlikely to be determined by a single major genetic cause,but rather by the interaction of multiple genes.At the same time,certain genetic factors seem to have more influence on special intermediate traits or endophenotypes than on the disease itself.Therefore,it may be a useful approach to integrate the multiple genetic risk factors with phenomenology in research into the pathogenesis of schizophrenia.
In a previous study,we tested the entire dopamine metabolic pathway and found that the combined effect of single-nucleotide polymorphisms(SNPs) in the genes encoding catechol-O-methyltransferase(COMT) and aldehyde dehydrogenase 3B1(ALDH3B1), two enzymes involved in the breakdown of dopamine,conferred a genetic susceptibility to paranoid schizophrenia.However,the diseased-associated SNPs were all intronic, making it difficult to explain the interaction pattern and precise mechanism by which these variants of the COMT and ALDH3B1 genes confer susceptibility to the disorder. We also found that the genes involved in that pathway may increase the susceptibility of some psychiatric symptoms.
According to the genetic characteristic of schizophrenia and our previous achievements,we carried out two researches in this thesis:1) to further explore the mechanism under the association of COMT and ALDH3B1 genes with paranoid schizophrenia;2) to explore the molecular etiology of auditory hallucination in schizophrenia.
In the first part of this study,we scanned all possible functional SNPs within these two genes by PCR-based genotyping analysis in 540 paranoid schizophrenics and 660 controls from a Han Chinese population.We also determined the effects of schizophrenia-associated SNPs on the development of psychotic symptoms,P300 event-related potential component induced by an auditory odd-ball task,and gene expression examined by quantitative real-time PCR analysis.The major findings of this study were that among the individuals carrying the rs3751082 A allele in the ALDH3B1 gene,the rs4633 T allele in the COMT gene was associated with susceptibility to paranoid schizophrenia(P=0.004),development of hallucinations(P=5.141 E-5), delay of P300 latency in both patients(P=0.006) and controls(P=0.02),and increased expression of the COMT gene in controls(P=0.002).However,the rs4633 T allele did not show any association in the rs3751082 G/G genotype carriers.
In the second part of this study,we firstly scanned the 47 SNPs in 27 genes in the dopamine signal pathway among 96 schizophrenics with auditory hallucination,96 schizophrenics without auditory hallucination and 108 controls.And found that the genotypic frequency of rs1700908 in CCKAR gene was distributed significantly differently between schizophrenics with and without hallucinations(Adjust P=0.02).To testify this result,we then make a throughout sequencing of CCKAR gene in another sample.And found that rs1800857-rs2071011 haplotype in CCKAR gene can increase the susceptibility of auditory hallucinations in the schizophrenics(Adjust P=0.003).
In the First part of this study,we not only guarantee the repeatability of genetic study, but also support the genetic results by several functions evidence,which can give a systematic view of the association of COMT and ALDH3B1 genes with paranoid schizophrenia.In the second part of the study,we start the work from auditory hallucination,which can control the stratification of samples.We also justified the genetic results by two-stage case-control study,which confirmed the association of CCKAR gene with auditory hallucination and bring new idea for the researches of psychiatric disorders.
多年来的研究表明,精神分裂症是一种典型的多基因复杂性状疾病,其中遗传因素所占的比重更大,遗传度可达80%,但是通过关联研究和连锁分析均未能找到确切的致病基因。这主要是因为精神分裂症临床分型复杂,症状多样,若将不同类型的患者混杂起来研究将难以对这种异质性疾病作出可信的结论;同时该病作为多基因病的一种,其发病是由许多微效基因共同作用决定的,若孤立地研究某个候选基因或候选染色体区域与疾病的关系,也难以得出满意的结果。这就需要在研究中,通过表型甚至内表型将样本纯化,并研究多个基因与疾病乃至表型的关系。另外,在本课题组前期工作中,以多巴胺代谢通路中涉及的基因为研究对象,发现位于儿茶酚胺氧位甲基转移酶(Catechol-O-methyltransferase,COMT)和乙醛脱氢酶(Aldehyde dehydrogenase 3B1,ALDH3B1)基因内含子区的两个单核苷酸多态性(Single Nucleotide Polymorphism,SNP)的联合作用,可以增高偏执型精神分裂症的易感性,同时也发现该通路中的基因与精神分裂症某些表型的发生相关。
综合精神分裂症的遗传学特点和课题组前期研究成果,本论文从两个方面对精神分裂症进行研究:1、进一步探索COMT和ALDH381基因的相互作用对偏执型精神分裂症发生的影响。2、以精神分裂症为切入点研究幻听表型的发生机制。
在第一部分工作中,我们在540例偏执型精神分裂症患者和660例对照中,筛查了两基因全部外显子中可能的功能SNPs,受试者均为中国北方汉族人群。对于筛查到的易感SNPs,检测其对于精神病性症状的影响,同时使用听觉odd-ball范式检测该易感SNPs对P300波幅和潜伏期的影响;使用Reai-time PCR的方法检测该易感SNPs对基因表达的影响。结果发现,只有在携带ALDH3B1 rs3751082-A等位基因的人群中,COMT rs4633-T等位基因与偏执型精神分裂症的易感性(P=0.004),幻觉的发生(P=5.141 E-5),患者(P=0.006)和对照(P=0.02)中P300潜伏期的延长,对照中COMT基因表达量的升高(P=0.002)显著相关;而在携带ALDH3B1 rs3751082 G/G基因型的人群中,却没有发现rs4633-T等位基因与以上各项指标的相关性。
在第二部分工作中,我们首先在96例具有和不具有幻听表型的精神分裂症患者和108例对照中,初步研究了多巴胺信号传导通路的27个基因的47个SNPs与幻听的关系。发现胆囊收缩素基因(cholycystokinin receptor A,CCKAR)rs1700908多态性在具有和不具有幻听表型的精神分裂症患者间分布具有显著差异(Adjust P=0.02)。为验证这一结果,在更大样本中对CCKAR基因进行了全面筛查。结果显示,CCKAR基因的rs1800857-rs2071011单倍型与幻听的发生相关(Adjust P=0.003)。
在第一部分工作中,我们不仅在遗传学水平上保证了结果的可重复性,而且在功能学水平上给予了多层面的证据支持,从而系统地阐释了COMT和ALDH3B1基因与精神分裂症的关系。在第二部分工作中,我们以幻听这一特异表型入手,严格控制样本分层,并且通过两阶段式病例-对照研究,和对阳性结果基因的全面筛查,证实了CCKAR基因与幻听表型的相关性,为精神分裂症的研究提供了新的思路。
Schizophrenia is a common yet severe psychiatric condition that affects about 1%of the population.The disorder always suffers the youth,and brings heavy economical and social burdens to families and societies.
After decades of study,schizophrenia is considered as a typical complex disorder. Although the genetic factors account for much of the etiology and the heredity of schizophrenia is over 80%,the candidate gene is still unknown after amounts of association and linkage studies.These studies are mainly complicated by complex genetic background and clinical heterogeneity.Schizophrenia is unlikely to be determined by a single major genetic cause,but rather by the interaction of multiple genes.At the same time,certain genetic factors seem to have more influence on special intermediate traits or endophenotypes than on the disease itself.Therefore,it may be a useful approach to integrate the multiple genetic risk factors with phenomenology in research into the pathogenesis of schizophrenia.
In a previous study,we tested the entire dopamine metabolic pathway and found that the combined effect of single-nucleotide polymorphisms(SNPs) in the genes encoding catechol-O-methyltransferase(COMT) and aldehyde dehydrogenase 3B1(ALDH3B1), two enzymes involved in the breakdown of dopamine,conferred a genetic susceptibility to paranoid schizophrenia.However,the diseased-associated SNPs were all intronic, making it difficult to explain the interaction pattern and precise mechanism by which these variants of the COMT and ALDH3B1 genes confer susceptibility to the disorder. We also found that the genes involved in that pathway may increase the susceptibility of some psychiatric symptoms.
According to the genetic characteristic of schizophrenia and our previous achievements,we carried out two researches in this thesis:1) to further explore the mechanism under the association of COMT and ALDH3B1 genes with paranoid schizophrenia;2) to explore the molecular etiology of auditory hallucination in schizophrenia.
In the first part of this study,we scanned all possible functional SNPs within these two genes by PCR-based genotyping analysis in 540 paranoid schizophrenics and 660 controls from a Han Chinese population.We also determined the effects of schizophrenia-associated SNPs on the development of psychotic symptoms,P300 event-related potential component induced by an auditory odd-ball task,and gene expression examined by quantitative real-time PCR analysis.The major findings of this study were that among the individuals carrying the rs3751082 A allele in the ALDH3B1 gene,the rs4633 T allele in the COMT gene was associated with susceptibility to paranoid schizophrenia(P=0.004),development of hallucinations(P=5.141 E-5), delay of P300 latency in both patients(P=0.006) and controls(P=0.02),and increased expression of the COMT gene in controls(P=0.002).However,the rs4633 T allele did not show any association in the rs3751082 G/G genotype carriers.
In the second part of this study,we firstly scanned the 47 SNPs in 27 genes in the dopamine signal pathway among 96 schizophrenics with auditory hallucination,96 schizophrenics without auditory hallucination and 108 controls.And found that the genotypic frequency of rs1700908 in CCKAR gene was distributed significantly differently between schizophrenics with and without hallucinations(Adjust P=0.02).To testify this result,we then make a throughout sequencing of CCKAR gene in another sample.And found that rs1800857-rs2071011 haplotype in CCKAR gene can increase the susceptibility of auditory hallucinations in the schizophrenics(Adjust P=0.003).
In the First part of this study,we not only guarantee the repeatability of genetic study, but also support the genetic results by several functions evidence,which can give a systematic view of the association of COMT and ALDH3B1 genes with paranoid schizophrenia.In the second part of the study,we start the work from auditory hallucination,which can control the stratification of samples.We also justified the genetic results by two-stage case-control study,which confirmed the association of CCKAR gene with auditory hallucination and bring new idea for the researches of psychiatric disorders.
引文
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