基于突触可塑性异常假说的重性精神障碍易感基因的分子遗传学研究
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摘要
精神障碍是一组以行为、心理活动上的紊乱为主要特征的神经系统疾病,具有低病死率和高致残率的特点。常见的重性精神障碍有精神分裂症、抑郁症、双相情感障碍和孤独症等。多项研究结果支持遗传因素在重性精神障碍的发生中具有重要作用,识别重性精神障碍的易感基因是当前重性精神障碍研究领域的关键问题之一。
目前针对重性精神障碍的发病机制提出了多种假说,为各种症状的成因提供了可能的解释,但尚未找到明确的易感基因,这种情况使人们开始重新评价现有的发病假说;同时,越来越多的证据表明重性精神障碍的发生与依赖NMDAR的突触可塑性异常相关。此外,临床异质性已经成为困扰精神疾病病因学研究的一大障碍。为了解决这一问题,在目前的研究中逐渐引入了“内表型”的概念。认知功能障碍普遍存在于重性精神疾病之中,大量的研究表明认知功能障碍可以作为精神疾病的内表型。
在本论文中,我们开展了两方面的研究。
第一方面的工作是在依赖NMDAR的LTP通路上进行精神分裂症易感基因的研究。我们先在96例精神分裂症患者和96例对照中,筛检了依赖于NMDAR的LTP通路上的14个候选基因的43个SNPs,共筛检到五个主要与疾病的易感性相关的SNPs,依次是G72基因的rs3916965,rs3916966和rs9558562及早老素—2基因(PSEN2)的rs1295645和rs6759。
随后我们在454例患者和480例对照中对这两个基因进行了扩大样本的验证,结果表明G72基因和PSEN2基因依然与精神分裂症相关。我们进一步采用实时定量PCR观察了两个基因在患者组和对照组转录水平的变化,结果显示患者组G72基因的表达与对照组相比显著升高,但未发现不同基因型间表达量的差异;患者PSEN2基因的表达较对照组明显降低,各SNPs的不同基因型间的表达量存在差异。此外,我们还采用条件检验进行两个基因的联合作用分析,结果表明G72基因和PSEN2基因存在联合作用。
第二方面的工作是以认知功能障碍为内表型,在依赖NMDA受体的LTP通路上进行重性精神疾病易感基因的研究。在这部分工作中,我们选用目前国际上较为常用的反映认知功能的3个神经心理测验(19项)对50例重性精神障碍患者(精神分裂症和抑郁症)和50例对照进行测定,比较患者组与对照组的认知功能,结果表明重性精神障碍患者存在明显的认知缺陷,包括智力、记忆和执行功能。之后结合依赖NMDAR的LTP通路上的14个候选基因,进行认知功能障碍的数量性状遗传学分析,结果表明AKT1,BDNF,CNTF,DISC1,EGF,G72,NOS1,NTF3和PSEN2与重性精神障碍患者的认知功能缺陷相关。
在本部分工作中G72基因和PSEN2基因再次被检出;AKT1,BDNF,CNTF,DISC1,EGF,NOS1和NTF3在上一部分未发现与精神分裂症相关,而以认知功能为内表型进行研究,得到阳性结果,说明内表型具有较高的灵敏性和检出率。
通过我们的研究,说明依赖NMDAR的LTP通路与重性精神障碍的易感性相关;以认知功能作为内表型,可以提高重性精神障碍(认知功能缺陷)易感基因的检出率。这些结果有可能为重性精神障碍的发病机制提供新的线索。
Mental disorders are characterized by the abnormal mental functions and disturbed behaviors with the low mortality and high disability.Common mental disorder included schizophrenia,depression,bipolar disorder,autism and so on.Several lines of evidence suggest that genetic factors are likely to play an essential role in developing of mental disorder.Now,the main challenge to genetic study is how to screen the predisposing genes of mental disorders.
Many hypotheses had been raised to explain the etiology of the symptoms. However the genes evoking mental disorder remain unclear.People began to evaluate the existent hypotheses.Now,more and more evidences suggest that there be some relationship between the abnormality of synaptic plasticity and mental disorder.In addition,clinical heterogeneity has been one of the obstacles in the study of the etiology of mental disorders.To solve this problem,the concept of endophenotype has been introduced to the present studies.Many evidences indicate Cognitive impairments maybe a representative endophenotype for mental disorders.
There are two parts in our work.
In the first part,we carried out the study of the predisposing genes related to the NMDAR-LTP pathway.We performed a two-step analysis.In the analytical step,we genotyped 43 reported single nucleotide polymorphisms(SNPs) present in 14 genes related to the NMDAR-LTP pathway among 96 paranoid schizophrenics and 96 normal controls.The results showed that five susceptibity SNPs sites were found to be associated with schizophrenia.The five SNPs were:rs3916965,rs3916966 and rs9558562 of the G72 gene;rs1295645 and rs6759 of the PSEN2 gene.The second step was to validate the initial findings in a larger sample size(454 schizophrenics and 484 controls).The G72 gene and the PSEN2 gene were also showed positive association with the disorder.In addition,analysis of gene expression demonstrated that G72 mRNA levels were significantly higher in the patient group than in control group.The expression levels of the G72 gene were not correlated to its genotypes;the PSEN2 mRNA levels were significantly lower in the patient group than in control group and that expression levels of the PSEN2 gene were significantly correlated to its genotypes.In addition,the combined effect of G72 and PSEN2 was found with the conditional test.
In the second part,we took the cognitive deficits as the endophenotype and carried out the study of the predisposing genes related to the NMDAR-LTP pathway,we collected the general and clinical data of 50 patients(25) and the general data of 50 normal controls.Then all the subjects are required to complete three sets of neuropsychological tests(19 items).The results show that there was significant difference between patients and normal controls in almost all of their performances of neuropsychological test,including intelligence,memory and executive functioning.Then combined with the 14 candidate genes on the NMDAR-LTP,the quantitive trait analysis of cognitive impairments was taken.The results show that there were 9 genes associated with cognitive impairments.The susceptibility genes were:AKT1,BDNF,CNTF, DISC1,EGF,G72,NOS1,NTF3和PSEN2.In this part,the G72 gene and the PSEN2 gene were detected again.The genes of AKT1,BDNF,CNTF,DISC1,EGF,NOS1 and NTF3 were caught,which indicated that the endophenotype were more sensitive.
Our study suggested that the NMDAR-LTP pathway is correlated with the susceptibility of mental disorder.With cognitive deficits as the endophenotype, susceptibility genes can be found with the cognitive deficits as the endophenotype.Our results may supply new clues for the study of the pathogenesis of major mental disorders.
目前针对重性精神障碍的发病机制提出了多种假说,为各种症状的成因提供了可能的解释,但尚未找到明确的易感基因,这种情况使人们开始重新评价现有的发病假说;同时,越来越多的证据表明重性精神障碍的发生与依赖NMDAR的突触可塑性异常相关。此外,临床异质性已经成为困扰精神疾病病因学研究的一大障碍。为了解决这一问题,在目前的研究中逐渐引入了“内表型”的概念。认知功能障碍普遍存在于重性精神疾病之中,大量的研究表明认知功能障碍可以作为精神疾病的内表型。
在本论文中,我们开展了两方面的研究。
第一方面的工作是在依赖NMDAR的LTP通路上进行精神分裂症易感基因的研究。我们先在96例精神分裂症患者和96例对照中,筛检了依赖于NMDAR的LTP通路上的14个候选基因的43个SNPs,共筛检到五个主要与疾病的易感性相关的SNPs,依次是G72基因的rs3916965,rs3916966和rs9558562及早老素—2基因(PSEN2)的rs1295645和rs6759。
随后我们在454例患者和480例对照中对这两个基因进行了扩大样本的验证,结果表明G72基因和PSEN2基因依然与精神分裂症相关。我们进一步采用实时定量PCR观察了两个基因在患者组和对照组转录水平的变化,结果显示患者组G72基因的表达与对照组相比显著升高,但未发现不同基因型间表达量的差异;患者PSEN2基因的表达较对照组明显降低,各SNPs的不同基因型间的表达量存在差异。此外,我们还采用条件检验进行两个基因的联合作用分析,结果表明G72基因和PSEN2基因存在联合作用。
第二方面的工作是以认知功能障碍为内表型,在依赖NMDA受体的LTP通路上进行重性精神疾病易感基因的研究。在这部分工作中,我们选用目前国际上较为常用的反映认知功能的3个神经心理测验(19项)对50例重性精神障碍患者(精神分裂症和抑郁症)和50例对照进行测定,比较患者组与对照组的认知功能,结果表明重性精神障碍患者存在明显的认知缺陷,包括智力、记忆和执行功能。之后结合依赖NMDAR的LTP通路上的14个候选基因,进行认知功能障碍的数量性状遗传学分析,结果表明AKT1,BDNF,CNTF,DISC1,EGF,G72,NOS1,NTF3和PSEN2与重性精神障碍患者的认知功能缺陷相关。
在本部分工作中G72基因和PSEN2基因再次被检出;AKT1,BDNF,CNTF,DISC1,EGF,NOS1和NTF3在上一部分未发现与精神分裂症相关,而以认知功能为内表型进行研究,得到阳性结果,说明内表型具有较高的灵敏性和检出率。
通过我们的研究,说明依赖NMDAR的LTP通路与重性精神障碍的易感性相关;以认知功能作为内表型,可以提高重性精神障碍(认知功能缺陷)易感基因的检出率。这些结果有可能为重性精神障碍的发病机制提供新的线索。
Mental disorders are characterized by the abnormal mental functions and disturbed behaviors with the low mortality and high disability.Common mental disorder included schizophrenia,depression,bipolar disorder,autism and so on.Several lines of evidence suggest that genetic factors are likely to play an essential role in developing of mental disorder.Now,the main challenge to genetic study is how to screen the predisposing genes of mental disorders.
Many hypotheses had been raised to explain the etiology of the symptoms. However the genes evoking mental disorder remain unclear.People began to evaluate the existent hypotheses.Now,more and more evidences suggest that there be some relationship between the abnormality of synaptic plasticity and mental disorder.In addition,clinical heterogeneity has been one of the obstacles in the study of the etiology of mental disorders.To solve this problem,the concept of endophenotype has been introduced to the present studies.Many evidences indicate Cognitive impairments maybe a representative endophenotype for mental disorders.
There are two parts in our work.
In the first part,we carried out the study of the predisposing genes related to the NMDAR-LTP pathway.We performed a two-step analysis.In the analytical step,we genotyped 43 reported single nucleotide polymorphisms(SNPs) present in 14 genes related to the NMDAR-LTP pathway among 96 paranoid schizophrenics and 96 normal controls.The results showed that five susceptibity SNPs sites were found to be associated with schizophrenia.The five SNPs were:rs3916965,rs3916966 and rs9558562 of the G72 gene;rs1295645 and rs6759 of the PSEN2 gene.The second step was to validate the initial findings in a larger sample size(454 schizophrenics and 484 controls).The G72 gene and the PSEN2 gene were also showed positive association with the disorder.In addition,analysis of gene expression demonstrated that G72 mRNA levels were significantly higher in the patient group than in control group.The expression levels of the G72 gene were not correlated to its genotypes;the PSEN2 mRNA levels were significantly lower in the patient group than in control group and that expression levels of the PSEN2 gene were significantly correlated to its genotypes.In addition,the combined effect of G72 and PSEN2 was found with the conditional test.
In the second part,we took the cognitive deficits as the endophenotype and carried out the study of the predisposing genes related to the NMDAR-LTP pathway,we collected the general and clinical data of 50 patients(25) and the general data of 50 normal controls.Then all the subjects are required to complete three sets of neuropsychological tests(19 items).The results show that there was significant difference between patients and normal controls in almost all of their performances of neuropsychological test,including intelligence,memory and executive functioning.Then combined with the 14 candidate genes on the NMDAR-LTP,the quantitive trait analysis of cognitive impairments was taken.The results show that there were 9 genes associated with cognitive impairments.The susceptibility genes were:AKT1,BDNF,CNTF, DISC1,EGF,G72,NOS1,NTF3和PSEN2.In this part,the G72 gene and the PSEN2 gene were detected again.The genes of AKT1,BDNF,CNTF,DISC1,EGF,NOS1 and NTF3 were caught,which indicated that the endophenotype were more sensitive.
Our study suggested that the NMDAR-LTP pathway is correlated with the susceptibility of mental disorder.With cognitive deficits as the endophenotype, susceptibility genes can be found with the cognitive deficits as the endophenotype.Our results may supply new clues for the study of the pathogenesis of major mental disorders.
引文
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