HDACs基因家族基因多态性与精神分裂症的关联性分析
发布时间：2018-10-13 11:48
【摘要】：精神分裂症是一种严重的精神疾病，多发于青壮年，严重威胁人类的身心健康，并给家庭和社会带来沉重的负担。精神分裂症在人群中的患病率约为1%，其病因及发病机制目前尚不明确。家系、双生子以及寄养子研究结果均表明遗传因素在精神分裂症的发病过程中起到重要作用，其遗传度为60%～80%。精神分裂症不符合传统的孟德尔遗传定律，不是单基因遗传病，可能是由多个微效或中效基因共同作用，并在一定程度上受环境因素影响的复杂多基因遗传疾病。本研究基于候选基因策略，选择在表观遗传学机制中起重要作用的组蛋白去乙酰化酶（HDACs）基因家族，，采用核心家系设计探讨HDACs基因家族基因多态性与精神分裂症的关系，该结果对于揭示精神分裂症的分子遗传学机制具有重要作用。 目的 利用生物信息学、分子生物学技术和先进的生物统计学等方法，探讨HDACs基因家族基因多态性与精神分裂症的关系。 方法 本研究以208例中国北方汉族精神分裂症患者及其416名健康父母双亲组成的核心家系作为研究对象，患者中男性125例，女性83例，利用生物信息学方法在HDACs基因家族上选择10个标签SNPs（tag SNPs）位点，包括HDAC2基因rs10499080、rs6568819、rs2499618和rs132044454个位点，HDAC3基因rs11741808和rs25302232个位点，HDAC8基因rs12690254、rs3012655、rs497551和rs5444844个位点。利用Sequenom MassArray质谱阵列技术检测个体基因型。应用拟合优度χ2检验计算基因型频数分布是否符合Hardy-Weinberg平衡定律；应用基于核心家系的关联分析方法[基于单倍体型的单倍体相对风险分析（HHRR）和连锁不平衡检验（TDT）]分析各位点与精神分裂症的关系；应用UNPHASED分析平台分析各位点之间连锁不平衡程度及单倍体分析；应用χ2检验分析HDACs基因家族基因上的10个tag SNPs位点与精神分裂症临床症状关联性；应用PGMDR软件分析HDAC2、HDAC3和HDAC8基因之间的交互作用与精神分裂症的关联。 结果 （1） Hardy-Weinberg平衡定律检验结果 HDAC2基因和HDAC3基因共选取的6个tag SNPs位点，除HDAC2基因rs10499080位点在对照组中的基因型频数分布不符合Hardy-Weinberg平衡定律（P＜0.05）外，其他5个tag SNPs位点基因型的频数分布均符合Hardy-Weinberg平衡定律（均P＞0.05），由于HDAC8基因位于X染色体，经Hardy-Weinberg平衡检验也证实该基因的4个tag SNPs位点患者组和对照组基因型分布均不符合Hardy-Weinberg平衡定律（均P＜0.05）。 （2） HHRR分析结果 HHRR分析结果显示：HDACs基因9个tag SNPs位点等位基因在“患者组”和“对照组”中的频数分布差异均无统计学意义（均P＞0.05），表明HDACs基因9个tag SNPs位点与精神分裂症无关联；在女性精神分裂症患者中，HDAC3基因rs11741808位点等位基因在“病例组”和“对照组”中的频数分布差异有统计学意义（P=0.039）。 （3） TDT分析结果 TDT分析结果显示：在总体样本中HDACs基因上的9个tag SNPs位点传递给患病子女的2个不同等位基因概率均未偏离50%（均P＞0.05），表明HDACs基因与精神分裂症无关联；在女性患者中HDAC3基因rs11741808位点传递给患病子女的2个不同等位基因概率偏离了50%（P=0.038）。 （4）多位点联合分析结果 HDAC2基因上的3个tag SNPs位点组成的3种单倍体型与精神分裂症无关联（均P＞0.05）;HDAC3基因上的2个tag SNPs位点组成1个单倍体型与精神分裂症无关联（P＞0.05）; HDAC8基因的4个tag SNPs位点组成的6种单倍体型与精神分裂症无关联（均P＞0.05）。 （5）临床症状关联性分析结果 在总体样本中，HDAC2基因rs13204445位点、HDAC3基因上rs11741808和rs2530223位点、HDAC8基因上的rs12690254、rs3012655、rs497551和rs544484位点与精神分裂症的阳性症状有关；HDAC3基因rs2530223位点与精神分裂症的阴性症状有关联。 在男性患者组中，HDAC2基因rs6568819和rs13204445位点、HDAC3基因上rs11741808和rs2530223、HDAC8基因上的rs12690254、rs3012655、rs497551和rs544484位点与精神分裂症的阳性症状相关联；HDAC3基因rs2530223位点和HDAC8基因rs3012655位点与精神分裂症的阴性症状相关联。 在女性患者组中，HDAC2基因rs6568819和rs2499618位点、HDAC3基因上rs2530223位点、HDAC8基因上的rs12690254、rs3012655、rs497551和rs544484位点与精神分裂症的阳性症状相关联；HDAC2基因rs2499618位点和HDAC8基因rs3012655位点与精神分裂症的阴性症状相关联。 （6）临床亚型关联性分析结果 在总体样本中，HDAC2和HDAC3基因上各位点与偏执型和未分型精神分裂症无关联。HDAC3基因rs11741808和rs2530223位点与偏执型精神分裂症相关联。 （7）基因-基因交互作用分析结果 利用PGMDR软件分析了HDAC2、HDAC3和HDAC8基因上的9个tag SNPs位点间的交互作用与精神分裂症的关联性，其结果显示5阶模型rs2530223-rs6568819-rs12690254-rs497551-rs544484为多因子基因-基因交互的最佳模型(P＜0.05），上述5个位点的交互作用与精神分裂症的发病相关联。 结论 由上述分析结果可以得到如下结论：①HDAC3基因rs11741808位点与女性精神分裂症相关联；②HDAC2、HDAC3和HDAC8基因可能与精神分裂症某些阳性症状和阴性症状相关联；③HDAC2、HDAC3和HDAC8基因存在多个位点与偏执型和未分型精神分裂症相关联；④rs2530223-rs6568819-rs12690254-rs497551-rs544484这5个位点的交互作用与精神分裂症有关；⑤精神分裂症存在遗传异质性和临床异质性。
[Abstract]:Schizophrenia is a serious mental illness, multiple in young adults, a serious threat to the physical and mental health of human beings, and a heavy burden on families and societies. The prevalence of schizophrenia in the population is about 1%, and the etiology and pathogenesis of schizophrenia are unclear. Results show that genetic factors play an important role in the pathogenesis of schizophrenia, and their genetic degree is 60% ~ 80%. Schizophrenia does not accord with the traditional Mendelian inheritance law, is not a single gene mutation, may be co-acting by a plurality of micro-effect or medium-effect genes, and is influenced by environmental factors to a certain extent. Based on the candidate gene strategy, this study selects the HACs gene family which plays an important role in the epigenetic mechanism, and uses the core family to design the relationship between the HDACs gene family gene polymorphism and schizophrenia. The results have an important role in revealing the molecular genetic mechanism of schizophrenia. Objective To explore the gene polymorphism and psychopathy of HDACs gene family by using bioinformatics, molecular biology techniques and advanced biostatistics methods. spadimia Methods The core family of 208 Chinese patients with schizophrenia and 416 healthy parents were studied in this study, including 125 males and 83 females, and 10 tags SNPs were selected on the HDACs gene family by using bioinformatics method. (tag SNPs) site, including HDAC2 gene rs10499080, rs6568819, rs2499618 and rs132044454 sites, HDAC3 gene rs11741808 and rs253022232 sites, HDAC8 gene rs12690254, rs3012655, rs497551 and r s5444844 sites. Using Sequenom MassArray mass spectrometry Detection of genotype in individual genotypes by array technique. The distribution of genotypic frequency distribution was calculated by using the goodness-of-fit test method 2. einberg equilibrium law; application of correlation analysis methods based on core family systems[haplotypes-based haplotype relative risk analysis (HHRR) and linkage disequilibrium test (TDT)] to analyze the relationship between individual points and schizophrenia; and use the UNPHASED analysis platform to analyze the linkage between the points. To analyze the correlation between the 10 tag SNPs loci on the HDACs gene family gene and the clinical symptoms of schizophrenia, and to analyze the interaction between HDAC2, HDAC3 and HDAC8 gene by using PGMDR software. function Association with schizophrenia. Results (1) Hard Results HDAC2 gene and HDAC3 gene were randomly divided into six tag SNPs loci, except that the genotype frequency distribution of HDAC2 gene rs10499080 locus in the control group was not in accordance with Hardy-W. In addition to the einberg equilibrium law (P <0.05), the frequency distribution of the genotypes of the other five tag SNPs was consistent with Hardy-Weinberg equilibrium law (P> 0.05). Because the HDAC8 gene was located on the X chromosome, the genotype distribution of the four tag SNPs loci and the genotype distribution of the control group were not consistent with the Hardy-Winberg equilibrium test. einberg equilibrium law (P <0.05). (2) HHRR analysis result HHRR analysis junction Fruit Display: H D ACs gene There was no significant difference in frequency distribution between 9 tag SNPs locus alleles in "patient group" and "control group" (P> 0.05), indicating that 9 tag SNPs sites of HDACs gene were not associated with schizophrenia; in a person, HD A C3 gene r S11741808 allele in "case group" and "pair Frequency distribution difference in group" There was statistical significance (P = 0.039). (3) TDT analysis showed that 9 tag SNPs sites on HDACs gene in the overall sample were transmitted to 2 different allele frequencies of diseased children. There was no association between HDACs gene and schizophrenia in 50% (P> 0.05). Hand to 2 different children of sick children There was no association between 3 haplotypes and schizophrenia (P> 0.05) and HDAC3 gene in HDAC2 gene. There was no association between 1 haploid type and schizophrenia (P> 0.05). 4 tag SNPs sites Six haplotypes were not associated with schizophrenia (all P> 0.05). (5) The results of correlation analysis of clinical symptoms were in the overall sample, rs13204445 of HDAC2 gene, rs11741808 and rs2530223 in HDAC3 gene, rs12690254, rs3012655, rs497551 and rs544484 in HDAC8 gene. The rs2530223 locus of the HDAC3 gene is associated with negative symptoms of schizophrenia. In the male patient group, the HDAC2 gene rs6568819 and rs13204445 sites, rs11741808 and rs2530223 on the HDAC3 gene, rs12690254, rs3012655, rs497551 and rs544484 at the HDAC8 gene are associated with positive symptoms of schizophrenia; HDAC The rs3012655 locus of the 3 gene rs2530223 and the HDAC8 gene are associated with negative symptoms of schizophrenia. In the female patient group, the HDAC2 gene rs6568819 and rs2499618, rs2530223 sites on the HDAC3 gene, rs12690254, rs3012655, rs497551 and rs544484 at the HDAC8 gene are associated with positive symptoms of schizophrenia; H DAC2 gene rs249961 The rs3012655 locus of the 8-site and HDAC8 gene was associated with negative symptoms of schizophrenia. (6) Clinical subtype association analysis results in the overall sample, on HDAC2 and HDAC3 genes, There was no association between the executive type and the unclassified schizophrenia. H DAC3 gene rs11741808 and rs2530223 locus were associated with paranoid schizophrenia. (7) The results of gene-gene interaction analysis used PGMDR software to analyze the association between the interaction of 9 tag SNPs sites on HDAC2, HDAC3 and HDAC8 genes and schizophrenia. The results showed that the 5th order model rs2530223-rs6568819-rs12690254-rs4 97 551-rs544484 is the best model for multi-factor gene-gene interaction (P <0.05). The interaction of the above five sites is associated with the onset of schizophrenia. Conclusion The results obtained from the above analysis can be concluded as follows: the hHDAC3 gene rs117 The 41808 locus is associated with female schizophrenia; the HDAC2, HDAC3, and HDAC8 genes may be associated with certain positive symptoms and negative symptoms of schizophrenia; the presence of multiple sites in the HDAC2, HDAC3, and HDAC8 genes is associated with paranoid and non-typing schizophrenia; Qrs2530223-rs656881
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R749.3
本文编号：2268505
[Abstract]:Schizophrenia is a serious mental illness, multiple in young adults, a serious threat to the physical and mental health of human beings, and a heavy burden on families and societies. The prevalence of schizophrenia in the population is about 1%, and the etiology and pathogenesis of schizophrenia are unclear. Results show that genetic factors play an important role in the pathogenesis of schizophrenia, and their genetic degree is 60% ~ 80%. Schizophrenia does not accord with the traditional Mendelian inheritance law, is not a single gene mutation, may be co-acting by a plurality of micro-effect or medium-effect genes, and is influenced by environmental factors to a certain extent. Based on the candidate gene strategy, this study selects the HACs gene family which plays an important role in the epigenetic mechanism, and uses the core family to design the relationship between the HDACs gene family gene polymorphism and schizophrenia. The results have an important role in revealing the molecular genetic mechanism of schizophrenia. Objective To explore the gene polymorphism and psychopathy of HDACs gene family by using bioinformatics, molecular biology techniques and advanced biostatistics methods. spadimia Methods The core family of 208 Chinese patients with schizophrenia and 416 healthy parents were studied in this study, including 125 males and 83 females, and 10 tags SNPs were selected on the HDACs gene family by using bioinformatics method. (tag SNPs) site, including HDAC2 gene rs10499080, rs6568819, rs2499618 and rs132044454 sites, HDAC3 gene rs11741808 and rs253022232 sites, HDAC8 gene rs12690254, rs3012655, rs497551 and r s5444844 sites. Using Sequenom MassArray mass spectrometry Detection of genotype in individual genotypes by array technique. The distribution of genotypic frequency distribution was calculated by using the goodness-of-fit test method 2. einberg equilibrium law; application of correlation analysis methods based on core family systems[haplotypes-based haplotype relative risk analysis (HHRR) and linkage disequilibrium test (TDT)] to analyze the relationship between individual points and schizophrenia; and use the UNPHASED analysis platform to analyze the linkage between the points. To analyze the correlation between the 10 tag SNPs loci on the HDACs gene family gene and the clinical symptoms of schizophrenia, and to analyze the interaction between HDAC2, HDAC3 and HDAC8 gene by using PGMDR software. function Association with schizophrenia. Results (1) Hard Results HDAC2 gene and HDAC3 gene were randomly divided into six tag SNPs loci, except that the genotype frequency distribution of HDAC2 gene rs10499080 locus in the control group was not in accordance with Hardy-W. In addition to the einberg equilibrium law (P <0.05), the frequency distribution of the genotypes of the other five tag SNPs was consistent with Hardy-Weinberg equilibrium law (P> 0.05). Because the HDAC8 gene was located on the X chromosome, the genotype distribution of the four tag SNPs loci and the genotype distribution of the control group were not consistent with the Hardy-Winberg equilibrium test. einberg equilibrium law (P <0.05). (2) HHRR analysis result HHRR analysis junction Fruit Display: H D ACs gene There was no significant difference in frequency distribution between 9 tag SNPs locus alleles in "patient group" and "control group" (P> 0.05), indicating that 9 tag SNPs sites of HDACs gene were not associated with schizophrenia; in a person, HD A C3 gene r S11741808 allele in "case group" and "pair Frequency distribution difference in group" There was statistical significance (P = 0.039). (3) TDT analysis showed that 9 tag SNPs sites on HDACs gene in the overall sample were transmitted to 2 different allele frequencies of diseased children. There was no association between HDACs gene and schizophrenia in 50% (P> 0.05). Hand to 2 different children of sick children There was no association between 3 haplotypes and schizophrenia (P> 0.05) and HDAC3 gene in HDAC2 gene. There was no association between 1 haploid type and schizophrenia (P> 0.05). 4 tag SNPs sites Six haplotypes were not associated with schizophrenia (all P> 0.05). (5) The results of correlation analysis of clinical symptoms were in the overall sample, rs13204445 of HDAC2 gene, rs11741808 and rs2530223 in HDAC3 gene, rs12690254, rs3012655, rs497551 and rs544484 in HDAC8 gene. The rs2530223 locus of the HDAC3 gene is associated with negative symptoms of schizophrenia. In the male patient group, the HDAC2 gene rs6568819 and rs13204445 sites, rs11741808 and rs2530223 on the HDAC3 gene, rs12690254, rs3012655, rs497551 and rs544484 at the HDAC8 gene are associated with positive symptoms of schizophrenia; HDAC The rs3012655 locus of the 3 gene rs2530223 and the HDAC8 gene are associated with negative symptoms of schizophrenia. In the female patient group, the HDAC2 gene rs6568819 and rs2499618, rs2530223 sites on the HDAC3 gene, rs12690254, rs3012655, rs497551 and rs544484 at the HDAC8 gene are associated with positive symptoms of schizophrenia; H DAC2 gene rs249961 The rs3012655 locus of the 8-site and HDAC8 gene was associated with negative symptoms of schizophrenia. (6) Clinical subtype association analysis results in the overall sample, on HDAC2 and HDAC3 genes, There was no association between the executive type and the unclassified schizophrenia. H DAC3 gene rs11741808 and rs2530223 locus were associated with paranoid schizophrenia. (7) The results of gene-gene interaction analysis used PGMDR software to analyze the association between the interaction of 9 tag SNPs sites on HDAC2, HDAC3 and HDAC8 genes and schizophrenia. The results showed that the 5th order model rs2530223-rs6568819-rs12690254-rs4 97 551-rs544484 is the best model for multi-factor gene-gene interaction (P <0.05). The interaction of the above five sites is associated with the onset of schizophrenia. Conclusion The results obtained from the above analysis can be concluded as follows: the hHDAC3 gene rs117 The 41808 locus is associated with female schizophrenia; the HDAC2, HDAC3, and HDAC8 genes may be associated with certain positive symptoms and negative symptoms of schizophrenia; the presence of multiple sites in the HDAC2, HDAC3, and HDAC8 genes is associated with paranoid and non-typing schizophrenia; Qrs2530223-rs656881
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R749.3
【参考文献】
相关期刊论文 前10条
1 汤毓华;张明元;;生活事件和精神分裂症[J];国外医学.精神病学分册;1987年01期
2 赵靖平,杨德森;精神分裂症单胺病理假说的药理学研究进展[J];国外医学.精神病学分册;1999年03期
3 朱芙蓉;郑英君;赵靖平;;精神分裂症的环境因素致病假说[J];国际精神病学杂志;2011年03期
4 陶领钢;黄峰;周云;李启斌;梁皓明;李广林;韦红日;周丽君;冯启明;;桂林市≥15岁城乡居民精神分裂症流行病学调查[J];广西医科大学学报;2011年06期
5 陈红梅;许小梅;栗克清;武浩然;李喜泼;;保定市精神分裂症性别差异的流行病学调查[J];神经疾病与精神卫生;2008年04期
6 王世纪,韦志岩,牛飞,张岿,韦学斌,张克民,程效芬,奚雪英,吴启英,刘青,宁南义,于世杰,高坤,刘恒芬,张新功,郭虹,郭翠玲,刘晓红,蔡贺云,彭学富;安徽阜阳市精神分裂症流行病学调查[J];临床精神医学杂志;2002年01期
7 汪广剑,陆伟玲,王焕林,仲爱芳,张理义,赵汉清,胡传荣;精神分裂症遗传的性别差异[J];临床精神医学杂志;2003年06期
8 何如东,周欢;基因组学在精神疾病的应用[J];临床精神医学杂志;2004年03期
9 邵臣,王德平,赵亚忠,姜松久,王守玉;大庆地区精神分裂症五年发病率调查[J];临床精神医学杂志;1997年06期
10 王娟;;人类基因组SNPs的研究现状及应用前景[J];生命科学;2006年04期
相关博士学位论文 前1条
1 程晖;全基因组关联研究搜寻中国汉族人银屑病易感基因[D];安徽医科大学;2011年
本文编号：2268505
本文链接：https://www.wllwen.com/yixuelunwen/jsb/2268505.html
最近更新
教材专著
