HDACs基因家族基因多態(tài)性與精神分裂癥的關(guān)聯(lián)性分析
發(fā)布時(shí)間：2018-10-13 11:48
【摘要】：精神分裂癥是一種嚴(yán)重的精神疾病，多發(fā)于青壯年，嚴(yán)重威脅人類的身心健康，并給家庭和社會(huì)帶來沉重的負(fù)擔(dān)。精神分裂癥在人群中的患病率約為1%，其病因及發(fā)病機(jī)制目前尚不明確。家系、雙生子以及寄養(yǎng)子研究結(jié)果均表明遺傳因素在精神分裂癥的發(fā)病過程中起到重要作用，其遺傳度為60%～80%。精神分裂癥不符合傳統(tǒng)的孟德爾遺傳定律，不是單基因遺傳病，可能是由多個(gè)微效或中效基因共同作用，并在一定程度上受環(huán)境因素影響的復(fù)雜多基因遺傳疾病。本研究基于候選基因策略，選擇在表觀遺傳學(xué)機(jī)制中起重要作用的組蛋白去乙�；福℉DACs）基因家族，，采用核心家系設(shè)計(jì)探討HDACs基因家族基因多態(tài)性與精神分裂癥的關(guān)系，該結(jié)果對(duì)于揭示精神分裂癥的分子遺傳學(xué)機(jī)制具有重要作用。 目的 利用生物信息學(xué)、分子生物學(xué)技術(shù)和先進(jìn)的生物統(tǒng)計(jì)學(xué)等方法，探討HDACs基因家族基因多態(tài)性與精神分裂癥的關(guān)系。 方法 本研究以208例中國(guó)北方漢族精神分裂癥患者及其416名健康父母雙親組成的核心家系作為研究對(duì)象，患者中男性125例，女性83例，利用生物信息學(xué)方法在HDACs基因家族上選擇10個(gè)標(biāo)簽SNPs（tag SNPs）位點(diǎn)，包括HDAC2基因rs10499080、rs6568819、rs2499618和rs132044454個(gè)位點(diǎn)，HDAC3基因rs11741808和rs25302232個(gè)位點(diǎn)，HDAC8基因rs12690254、rs3012655、rs497551和rs5444844個(gè)位點(diǎn)。利用Sequenom MassArray質(zhì)譜陣列技術(shù)檢測(cè)個(gè)體基因型。應(yīng)用擬合優(yōu)度χ2檢驗(yàn)計(jì)算基因型頻數(shù)分布是否符合Hardy-Weinberg平衡定律；應(yīng)用基于核心家系的關(guān)聯(lián)分析方法[基于單倍體型的單倍體相對(duì)風(fēng)險(xiǎn)分析（HHRR）和連鎖不平衡檢驗(yàn)（TDT）]分析各位點(diǎn)與精神分裂癥的關(guān)系；應(yīng)用UNPHASED分析平臺(tái)分析各位點(diǎn)之間連鎖不平衡程度及單倍體分析；應(yīng)用χ2檢驗(yàn)分析HDACs基因家族基因上的10個(gè)tag SNPs位點(diǎn)與精神分裂癥臨床癥狀關(guān)聯(lián)性；應(yīng)用PGMDR軟件分析HDAC2、HDAC3和HDAC8基因之間的交互作用與精神分裂癥的關(guān)聯(lián)。 結(jié)果 （1） Hardy-Weinberg平衡定律檢驗(yàn)結(jié)果 HDAC2基因和HDAC3基因共選取的6個(gè)tag SNPs位點(diǎn)，除HDAC2基因rs10499080位點(diǎn)在對(duì)照組中的基因型頻數(shù)分布不符合Hardy-Weinberg平衡定律（P＜0.05）外，其他5個(gè)tag SNPs位點(diǎn)基因型的頻數(shù)分布均符合Hardy-Weinberg平衡定律（均P＞0.05），由于HDAC8基因位于X染色體，經(jīng)Hardy-Weinberg平衡檢驗(yàn)也證實(shí)該基因的4個(gè)tag SNPs位點(diǎn)患者組和對(duì)照組基因型分布均不符合Hardy-Weinberg平衡定律（均P＜0.05）。 （2） HHRR分析結(jié)果 HHRR分析結(jié)果顯示：HDACs基因9個(gè)tag SNPs位點(diǎn)等位基因在“患者組”和“對(duì)照組”中的頻數(shù)分布差異均無統(tǒng)計(jì)學(xué)意義（均P＞0.05），表明HDACs基因9個(gè)tag SNPs位點(diǎn)與精神分裂癥無關(guān)聯(lián)；在女性精神分裂癥患者中，HDAC3基因rs11741808位點(diǎn)等位基因在“病例組”和“對(duì)照組”中的頻數(shù)分布差異有統(tǒng)計(jì)學(xué)意義（P=0.039）。 （3） TDT分析結(jié)果 TDT分析結(jié)果顯示：在總體樣本中HDACs基因上的9個(gè)tag SNPs位點(diǎn)傳遞給患病子女的2個(gè)不同等位基因概率均未偏離50%（均P＞0.05），表明HDACs基因與精神分裂癥無關(guān)聯(lián)；在女性患者中HDAC3基因rs11741808位點(diǎn)傳遞給患病子女的2個(gè)不同等位基因概率偏離了50%（P=0.038）。 （4）多位點(diǎn)聯(lián)合分析結(jié)果 HDAC2基因上的3個(gè)tag SNPs位點(diǎn)組成的3種單倍體型與精神分裂癥無關(guān)聯(lián)（均P＞0.05）;HDAC3基因上的2個(gè)tag SNPs位點(diǎn)組成1個(gè)單倍體型與精神分裂癥無關(guān)聯(lián)（P＞0.05）; HDAC8基因的4個(gè)tag SNPs位點(diǎn)組成的6種單倍體型與精神分裂癥無關(guān)聯(lián)（均P＞0.05）。 （5）臨床癥狀關(guān)聯(lián)性分析結(jié)果 在總體樣本中，HDAC2基因rs13204445位點(diǎn)、HDAC3基因上rs11741808和rs2530223位點(diǎn)、HDAC8基因上的rs12690254、rs3012655、rs497551和rs544484位點(diǎn)與精神分裂癥的陽性癥狀有關(guān)；HDAC3基因rs2530223位點(diǎn)與精神分裂癥的陰性癥狀有關(guān)聯(lián)。 在男性患者組中，HDAC2基因rs6568819和rs13204445位點(diǎn)、HDAC3基因上rs11741808和rs2530223、HDAC8基因上的rs12690254、rs3012655、rs497551和rs544484位點(diǎn)與精神分裂癥的陽性癥狀相關(guān)聯(lián)；HDAC3基因rs2530223位點(diǎn)和HDAC8基因rs3012655位點(diǎn)與精神分裂癥的陰性癥狀相關(guān)聯(lián)。 在女性患者組中，HDAC2基因rs6568819和rs2499618位點(diǎn)、HDAC3基因上rs2530223位點(diǎn)、HDAC8基因上的rs12690254、rs3012655、rs497551和rs544484位點(diǎn)與精神分裂癥的陽性癥狀相關(guān)聯(lián)；HDAC2基因rs2499618位點(diǎn)和HDAC8基因rs3012655位點(diǎn)與精神分裂癥的陰性癥狀相關(guān)聯(lián)。 （6）臨床亞型關(guān)聯(lián)性分析結(jié)果 在總體樣本中，HDAC2和HDAC3基因上各位點(diǎn)與偏執(zhí)型和未分型精神分裂癥無關(guān)聯(lián)。HDAC3基因rs11741808和rs2530223位點(diǎn)與偏執(zhí)型精神分裂癥相關(guān)聯(lián)。 （7）基因-基因交互作用分析結(jié)果 利用PGMDR軟件分析了HDAC2、HDAC3和HDAC8基因上的9個(gè)tag SNPs位點(diǎn)間的交互作用與精神分裂癥的關(guān)聯(lián)性，其結(jié)果顯示5階模型rs2530223-rs6568819-rs12690254-rs497551-rs544484為多因子基因-基因交互的最佳模型(P＜0.05），上述5個(gè)位點(diǎn)的交互作用與精神分裂癥的發(fā)病相關(guān)聯(lián)。 結(jié)論 由上述分析結(jié)果可以得到如下結(jié)論：①HDAC3基因rs11741808位點(diǎn)與女性精神分裂癥相關(guān)聯(lián)；②HDAC2、HDAC3和HDAC8基因可能與精神分裂癥某些陽性癥狀和陰性癥狀相關(guān)聯(lián)；③HDAC2、HDAC3和HDAC8基因存在多個(gè)位點(diǎn)與偏執(zhí)型和未分型精神分裂癥相關(guān)聯(lián)；④rs2530223-rs6568819-rs12690254-rs497551-rs544484這5個(gè)位點(diǎn)的交互作用與精神分裂癥有關(guān)；⑤精神分裂癥存在遺傳異質(zhì)性和臨床異質(zhì)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
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.3
本文編號(hào)：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
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.3
【參考文獻(xiàn)】
相關(guān)期刊論文 前10條
1 湯毓華;張明元;;生活事件和精神分裂癥[J];國(guó)外醫(yī)學(xué).精神病學(xué)分冊(cè);1987年01期
2 趙靖平,楊德森;精神分裂癥單胺病理假說的藥理學(xué)研究進(jìn)展[J];國(guó)外醫(yī)學(xué).精神病學(xué)分冊(cè);1999年03期
3 朱芙蓉;鄭英君;趙靖平;;精神分裂癥的環(huán)境因素致病假說[J];國(guó)際精神病學(xué)雜志;2011年03期
4 陶領(lǐng)鋼;黃峰;周云;李啟斌;梁皓明;李廣林;韋紅日;周麗君;馮啟明;;桂林市≥15歲城鄉(xiāng)居民精神分裂癥流行病學(xué)調(diào)查[J];廣西醫(yī)科大學(xué)學(xué)報(bào);2011年06期
5 陳紅梅;許小梅;栗克清;武浩然;李喜潑;;保定市精神分裂癥性別差異的流行病學(xué)調(diào)查[J];神經(jīng)疾病與精神衛(wèi)生;2008年04期
6 王世紀(jì),韋志巖,牛飛,張巋,韋學(xué)斌,張克民,程效芬,奚雪英,吳啟英,劉青,寧南義,于世杰,高坤,劉恒芬,張新功,郭虹,郭翠玲,劉曉紅,蔡賀云,彭學(xué)富;安徽阜陽市精神分裂癥流行病學(xué)調(diào)查[J];臨床精神醫(yī)學(xué)雜志;2002年01期
7 汪廣劍,陸偉玲,王煥林,仲愛芳,張理義,趙漢清,胡傳榮;精神分裂癥遺傳的性別差異[J];臨床精神醫(yī)學(xué)雜志;2003年06期
8 何如東,周歡;基因組學(xué)在精神疾病的應(yīng)用[J];臨床精神醫(yī)學(xué)雜志;2004年03期
9 邵臣,王德平,趙亞忠,姜松久,王守玉;大慶地區(qū)精神分裂癥五年發(fā)病率調(diào)查[J];臨床精神醫(yī)學(xué)雜志;1997年06期
10 王娟;;人類基因組SNPs的研究現(xiàn)狀及應(yīng)用前景[J];生命科學(xué);2006年04期
相關(guān)博士學(xué)位論文 前1條
1 程暉;全基因組關(guān)聯(lián)研究搜尋中國(guó)漢族人銀屑病易感基因[D];安徽醫(yī)科大學(xué);2011年
本文編號(hào)：2268505
本文鏈接：http://sikaile.net/yixuelunwen/jsb/2268505.html
最近更新
教材專著
