HDACs基因家族基因多态性与精神分裂症的关联性分析
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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。
Schizophrenia is a serious mental disease, which occurs in young adulthood. Itseriously threatens human being's mental and physical health and brings heavyeconomic burden to the society and families. The prevalence of schizophrenia incrowd is about1%, and until now the etiology and pathogenesis of schizophrenia arenot clear. The research of family, twin, and foster sub-study showed that geneticfactors played an important role in the pathogenesis of schizophrenia, with theheritability of60%to80%. Schizophrenia not only does not match the traditionalMendelian inheritance, but also it is not a single-gene genetic disease. It may becaused by the co-function of the multi-gene or minor genes together, and to someextent, it maybe influenced by environmental factors which played a role in theprogress of the disease occurring. Based on candidate gene strategy, histonedeacetylases (HDACs) family genes which played a very important role in epigeneticmechanism were selected to explore the associations between HDACs polymorphismsand schizophrenia by family trios. The results of our study would be useful to showmechanism of molecular genetics of schizophrenia.
Purpose
The purpose of our study is to explore the associations between HDACs familygenes polymorphisms and schizophrenia by the methods of the advancedbioinformatics, molecular biology and biostatistics. We aim to reveal the possiblemolecular genetics mechanism of the susceptibility genes of schizophrenia.Method
A total of208family trios consisting of fathers, mothers and affected offspring withschizophrenia were recruited as subject. There were125males and83females inpatients. Bioinformatics methods was used to select10tag HDACs SNPs, including4SNPs on HDAC2(rs10499080, rs6568819, rs2499618and rs13204445),2SNPs onHDAC3(rs11741808and rs2530223) and4SNPs on HDAC8(rs12690254,rs3012655, rs497551and rs544484). Sequenom Mass Array mass spectrometry array was performed to detect the individual genotype and allele. The chi-square (χ2)goodness-of-fit test was used to analyze the Hardy-Weinberg equilibrium (HWE) forgenotypic distribution. Allelic association for a single tag SNP was analyzed byfamily-based association tests, including the haplotype-based haplotype relative risk(HHRR) test and the transmission disequilibrium test (TDT). UNPHASED analysisplatform was used to test the balance level between the two sites and haplotype. Thechi-square test was used to test the associations between the10tag SNPs on theHDACs family genes and clinical symptoms and clinical subgroups of theschizophrenia. The PGMDR software was used to test the gene-gene interactions ofthe HDACs gene with schizophrenia.
Result
(1) Hardy-Weinberg equilibrium test
Six tag SNPs on the HDAC2and HDAC3were selected. Except for thers10499080on HDAC2, the genotype frequencies of the other five tag SNPs were allin Hardy-Weinberg equilibrium (P>0.05). Because HDAC8was located on Xchromosome, the genotype frequencies of four tag SNPs on it were not inHardy-Weinberg equilibrium (P <0.05).
(2) HHRR analysis
The results of the HHRR analysis showed that the frequent distributions of nine tagSNPs allele gene on HDACs between the patient group and their parents group werenot statistically different (all P>0.05), which revealed that there were no associationsbetween these nine tag SNPs on HDACs and schizophrenia. Among female patients,the frequent distribution of rs3012655on HDAC8was significantly different(P=0.039) between case group and control group.
(3) TDT analysis
The results of TDT analysis showed that the probabilities of two different alleleswhich transmitted from heterozygotic parents to affected offsprings did not biasedfrom50%(P>0.05). It revealed that there was no association between HDACs geneand schizophrenia. We also found that two different alleles of rs11741808on HDAC3transmitted from heterozygotic parents to affected offsprings biased from50%infemale patients (P=0.038).
(4) Multi-point combination analysis
The frequent distributions of three types of haplotype of the three tag HDAC2 SNPs, one haplotype of HDAC3, and six types of haplotype of thefour tag HDAC8SNPs were not significantly associated with schizophrenia (P>0.05).
(5) Correlation analysis of clinical symptoms and schizophrenia
In total sample, locus of rs13204445on HDAC2, loci of rs11741808and rs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms of schizophrenia. Locus ofrs2530223on HDAC3was significantly correlated with negative symptom of
schizophrenia.
Among male patients, loci of rs6568819and rs13204445on HDAC2, loci ofrs11741808and rs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms ofschizophrenia. Loci of rs2530223on HDAC3and rs3012655on HDAC8weresignificantly correlated with negative symptom of schizophrenia.
Among female patients, loci of rs6568819and rs2499618on HDAC2, locus ofrs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms of schizophrenia.Loci of rs2499618on HDAC2and rs3012655on HDAC8were significantlycorrelated with negative symptom of schizophrenia.
(6) Correlation analysis of clinical subtypes and schizophrenia.
In total sample, all the loci of HDAC2and HDAC3were not significantlyassociated with paranoid schizophrenia and unclassified schizophrenia. Loci ofrs11741808and rs2530223on HDAC3were significantly correlated with paranoidschizophrenia.
(7) Interactions between genes
PGMDR software was performed to analyze interactions between nine tag SNPs onHDAC2, HDAC3and HDAC8, respectively. The results showed that five-stagemultiple gene interaction model of rs2530223-rs6568819-rs12690254-rs497551-rs544484was the optimal model (P<0.05) to show associations between genes andschizophrenia.
Conclusion
Above all, five pointed were concluded:(1) locus of rs3012655on HDAC3wereassociated with schizophrenia among females;(2) HDAC2, HDAC3and HDAC8might associated with some positive symptoms and negative symptoms of schizophrenia;(3) some loci on HDAC2, HDAC3and HDAC8might associated withparanoid schizophrenia and unclassified schizophrenia;(4) interactions betweenrs2530223-rs6568819-rs12690254-rs497551-rs544484might associated withschizophrenia;(5) there were genetically heterogeneous and clinical heterogeneity inschizophrenia.
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。
Schizophrenia is a serious mental disease, which occurs in young adulthood. Itseriously threatens human being's mental and physical health and brings heavyeconomic burden to the society and families. The prevalence of schizophrenia incrowd is about1%, and until now the etiology and pathogenesis of schizophrenia arenot clear. The research of family, twin, and foster sub-study showed that geneticfactors played an important role in the pathogenesis of schizophrenia, with theheritability of60%to80%. Schizophrenia not only does not match the traditionalMendelian inheritance, but also it is not a single-gene genetic disease. It may becaused by the co-function of the multi-gene or minor genes together, and to someextent, it maybe influenced by environmental factors which played a role in theprogress of the disease occurring. Based on candidate gene strategy, histonedeacetylases (HDACs) family genes which played a very important role in epigeneticmechanism were selected to explore the associations between HDACs polymorphismsand schizophrenia by family trios. The results of our study would be useful to showmechanism of molecular genetics of schizophrenia.
Purpose
The purpose of our study is to explore the associations between HDACs familygenes polymorphisms and schizophrenia by the methods of the advancedbioinformatics, molecular biology and biostatistics. We aim to reveal the possiblemolecular genetics mechanism of the susceptibility genes of schizophrenia.Method
A total of208family trios consisting of fathers, mothers and affected offspring withschizophrenia were recruited as subject. There were125males and83females inpatients. Bioinformatics methods was used to select10tag HDACs SNPs, including4SNPs on HDAC2(rs10499080, rs6568819, rs2499618and rs13204445),2SNPs onHDAC3(rs11741808and rs2530223) and4SNPs on HDAC8(rs12690254,rs3012655, rs497551and rs544484). Sequenom Mass Array mass spectrometry array was performed to detect the individual genotype and allele. The chi-square (χ2)goodness-of-fit test was used to analyze the Hardy-Weinberg equilibrium (HWE) forgenotypic distribution. Allelic association for a single tag SNP was analyzed byfamily-based association tests, including the haplotype-based haplotype relative risk(HHRR) test and the transmission disequilibrium test (TDT). UNPHASED analysisplatform was used to test the balance level between the two sites and haplotype. Thechi-square test was used to test the associations between the10tag SNPs on theHDACs family genes and clinical symptoms and clinical subgroups of theschizophrenia. The PGMDR software was used to test the gene-gene interactions ofthe HDACs gene with schizophrenia.
Result
(1) Hardy-Weinberg equilibrium test
Six tag SNPs on the HDAC2and HDAC3were selected. Except for thers10499080on HDAC2, the genotype frequencies of the other five tag SNPs were allin Hardy-Weinberg equilibrium (P>0.05). Because HDAC8was located on Xchromosome, the genotype frequencies of four tag SNPs on it were not inHardy-Weinberg equilibrium (P <0.05).
(2) HHRR analysis
The results of the HHRR analysis showed that the frequent distributions of nine tagSNPs allele gene on HDACs between the patient group and their parents group werenot statistically different (all P>0.05), which revealed that there were no associationsbetween these nine tag SNPs on HDACs and schizophrenia. Among female patients,the frequent distribution of rs3012655on HDAC8was significantly different(P=0.039) between case group and control group.
(3) TDT analysis
The results of TDT analysis showed that the probabilities of two different alleleswhich transmitted from heterozygotic parents to affected offsprings did not biasedfrom50%(P>0.05). It revealed that there was no association between HDACs geneand schizophrenia. We also found that two different alleles of rs11741808on HDAC3transmitted from heterozygotic parents to affected offsprings biased from50%infemale patients (P=0.038).
(4) Multi-point combination analysis
The frequent distributions of three types of haplotype of the three tag HDAC2 SNPs, one haplotype of HDAC3, and six types of haplotype of thefour tag HDAC8SNPs were not significantly associated with schizophrenia (P>0.05).
(5) Correlation analysis of clinical symptoms and schizophrenia
In total sample, locus of rs13204445on HDAC2, loci of rs11741808and rs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms of schizophrenia. Locus ofrs2530223on HDAC3was significantly correlated with negative symptom of
schizophrenia.
Among male patients, loci of rs6568819and rs13204445on HDAC2, loci ofrs11741808and rs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms ofschizophrenia. Loci of rs2530223on HDAC3and rs3012655on HDAC8weresignificantly correlated with negative symptom of schizophrenia.
Among female patients, loci of rs6568819and rs2499618on HDAC2, locus ofrs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms of schizophrenia.Loci of rs2499618on HDAC2and rs3012655on HDAC8were significantlycorrelated with negative symptom of schizophrenia.
(6) Correlation analysis of clinical subtypes and schizophrenia.
In total sample, all the loci of HDAC2and HDAC3were not significantlyassociated with paranoid schizophrenia and unclassified schizophrenia. Loci ofrs11741808and rs2530223on HDAC3were significantly correlated with paranoidschizophrenia.
(7) Interactions between genes
PGMDR software was performed to analyze interactions between nine tag SNPs onHDAC2, HDAC3and HDAC8, respectively. The results showed that five-stagemultiple gene interaction model of rs2530223-rs6568819-rs12690254-rs497551-rs544484was the optimal model (P<0.05) to show associations between genes andschizophrenia.
Conclusion
Above all, five pointed were concluded:(1) locus of rs3012655on HDAC3wereassociated with schizophrenia among females;(2) HDAC2, HDAC3and HDAC8might associated with some positive symptoms and negative symptoms of schizophrenia;(3) some loci on HDAC2, HDAC3and HDAC8might associated withparanoid schizophrenia and unclassified schizophrenia;(4) interactions betweenrs2530223-rs6568819-rs12690254-rs497551-rs544484might associated withschizophrenia;(5) there were genetically heterogeneous and clinical heterogeneity inschizophrenia.
引文
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