摘要
精神分裂症是最常见、最严重的精神性疾病，多发于青壮年，世界人口中患病率约为1%；主要表现为精神活动与现实环境想脱离、认知、情感、意志及个性特征等各个方面不协调、相互分裂的疾病。精神分裂症发病主要受环境和遗传两大因素影响。家系、双生子及寄养子研究结果均表明遗传因素在其发病中具有重要作用。精神分裂症基因组扫描和候选基因研究，虽获得不少阳性结果，但重复性较差，结果争议很大。精神分裂症临床症状和认知功能受诸多因素影响，其遗传因素将会备受关注。
目的
利用生物信息学、分子遗传学技术及生物统计学方法，一方面探讨DBH、ACE、COMT、DRD2、CHRNA5、IL-10、IL-18、COX-2、TCF4、CACNA1C、MTHFR及GNB1L候选基因上SNPs与精神分裂症关联性，另一方面检验这些SNPs是否影响受试者临床症状和认知功能，试图揭示精神分裂症易感基因及影响临床症状和认知功能的遗传机制。
方法
本研究以350例首发精神分裂症，567例慢性精神分裂症和421例健康对照为研究对象。精神分裂症患者来自北京回龙观医院住院部，正常健康人群来自当地社区。所有研究对象均为中国汉族人，并且精神分裂症患者要符合ICD-10和CCMD-II-R的诊断标准。
在征得受试者知情同意的情况下，采集外周静脉血，采用Promega (USA)液体纯化提取DNA试剂盒，提取基因组DNA。利用PCR-AFLP和SequenomMassArray技术，检测12个候选基因13个SNPs位点（rs141116007、rs4340、rs4680、rs1800497、rs3829787、rs1800872、rs1946518、rs689466、rs5275、rs2958182、rs2239050、rs1801133和rs748806）。
应用在线遗传统计SHEsis软件计算基因型频率分布是否符合Hardy-Weinberg平衡定律；分析候选基因SNPs位点与精神分裂症的关联性；分析基因各个位点之间连锁不平衡程度及单倍型；应用MDR软件分析基因-基因间的交互作用；应用SPSS17.0软件分析候选基因SNPs位点与精神分裂症临床症状和认知功能的相关性。结果
1, H-W平衡检验和连锁不平衡程度分析
（1）H-W平衡检验
rs4340、rs3829787和rs5275位点的基因型分布在首发精神分裂症组中偏离H-W平衡；rs1800497、rs3829787和rs1801133位点的基因型分布在慢性精神分裂症组中偏离H-W平衡；说明这些位点可能是疾病易感SNPs位点或与易感SNPs连锁；其他位点基因型分布在首发精神分裂症组、慢性精神分裂症组和健康对照组中均符合H-W平衡定律（all, P＞0.05），说明本研究抽样样本符合遗传学分析。
（2）连锁不平衡程度分析
rs689466和rs5275处于高度连锁不平衡染色体区，说明其位于连锁不平衡区域内。
2，病例-对照分析
(1)首发精神分裂症-正常对照组单个SNP分析
rs141116007和rs5275位点与精神分裂症发病相关联，其等位基因和基因型频率分布在病例组和对照组中均出现显著性差异（all, P<0.05）。rs2239050和rs3829787位点可能与精神分裂症发病相关联。rs2239050等位基因和rs3829787基因型的频率分布在病例组和对照组中出现显著差异（both, P<0.05）。
(2)慢性精神分裂症-正常对照组单个SNP分析
rs4340、rs1801133和rs748806位点与精神分裂症发病相关联，其等位基因和基因型频率分布在两组中均出现显著性差异（all, P<0.05）。rs1800497位点可能与精神分裂症发病相关联，其基因型频率分布在病例组和对照组中出现显著差异（P<0.05）。
(3)病例对照组单倍型分析
对COX-2基因的2个SNPs位点进行联合分析。结果显示，仅rs689466(C)-rs5275(A)作为保护型单倍型与首发精神分裂症相关联（P<0.05）。
3，SNPs与精神分裂症临床症状的相关分析
(1) SNPs与首发精神分裂症临床症状的相关分析
在首发精神分裂症中，DBH基因rs141116007位点和IL18基因rs1946518位点与首发精神分裂症阳性症状和临床症状总分相关（all, P<0.05）；ACE基因rs4340位点与首发精神分裂症阴性症状相关（P<0.05）。
(2) SNPs与慢性精神分裂症临床症状的相关分析
在慢性精神分裂症中，COX-2基因rs689466和rs5275位点与慢性精神分裂症的阳性症状相关（both, P<0.05）；TCF4基因rs2958182位点与慢性精神分裂症阴性症状相关（P<0.05）；IL-18基因rs1946518位点与慢性精神分裂症临床症状总分相关（P<0.05）。
4，SNPs与认知功能的相关分析
(1) SNPs与正常健康人认知功能的相关分析
在正常健康对照中，TCF4基因rs2958182和CACNA1C基因rs2239050位点与正常健康人认知功能的注意相关（both, P<0.05）；COX-2基因rs5275位点与正常健康人认知功能的语言相关（P<0.05）；TCF4基因rs2958182位点与正常健康人认知功能的延迟记忆和总分值相关（both, P<0.05）。
(2) SNPs与首发精神分裂症认知功能的相关分析
在首发精神分裂症中，DBH基因rs141116007、DRD2基因rs1800497位点和COX-2基因rs5275位点与首发精神分裂症认知功能的即刻记忆相关（all,P<0.05）；COX-2基因rs689466位点和rs5275位点与首发精神分裂症认知功能的语言相关（all, P<0.05）。
(3) SNPs与慢性精神分裂症认知功能的相关分析
在慢性精神分裂症中，MTHFR基因rs18001133位点和IL-10基因rs1800872位点与慢性精神分裂症注意能力相关（both, P<0.05）；TCF4基因rs2958182位点和MTHFR基因rs18001133位点与慢性精神分裂症的语言能力相关（both,P<0.05）；DRD2基因rs1800497位点和TCF4基因rs2958182位点与慢性精神分裂症认知功能的延迟记忆相关（both, P<0.05）；TCF4基因rs2958182位点与慢性精神分裂症认知功能的总分值相关（P<0.05）。
结论
从上述分析可得到如下结论：(1) DBH、COX-2、CHRNA5和CACAN1C基因可能是首发精神分裂症的易感基因；（2）ACE、DRD2、MTHFR和GNB1L基因可能是慢性精神分裂症的易感基因；(3)首发精神分裂症中DBH、IL-18基因和慢性精神分裂症中COX-2基因分别与阳性症状相关（；4）首发精神分裂症中ACE基因和慢性精神分裂症中TCF4基因分别与阴性症状相关；（5）首发精神分裂症中DBH、IL-18基因和慢性精神分裂症中IL-18基因分别与临床症状总分相关；（6）TCF4、CACNA1C和COX-2基因与正常健康人群认知功能功能相关；（7）DBH、DRD2和COX-2基因与首发精神分裂症认知功能相关（；8）MTHFR、IL-10、DRD2、TCF4基因与慢性精神分裂症认知功能相关。（9）精神分裂症存在遗传和临床的异质性。
Schizophrenia is a common and serious mental disorder, which occurs in youngadulthood and whose prevalence in the general population worldwide is about1%. Itis characted by the abnormal mental functions and disturbed behaviors, whichcharacteristically appear as a series of clinical features, such as positive and negativesymptoms, and cognitive deficits. Its etiology has two mainly contributing factorsincluding environmental and genetic factors. Family, twins and adoptive studies haveprecisely indicated that genetic factors may be involved in schizophrenia. Studies ofschizophrenia on genome scanning and candidate genes have acquired many positiveresults, but most of these results produce poor replication. The clinical symptoms andcognitive functions of schizophrenia are contributed by many factors that the geneticfactors of which will be the research focus in the future.
Objective
One purpose of this study is to investigate the associations between schizophreniaand polymorphisms of12genes, including DBH, ACE, COMT, DRD2, CHRNA5,IL-10, IL-18, COX-2, TCF4, CACNA1C, MTHFR and GNB1L by the methods of thebioinformatics, molecular biology and biostatistics. The other purpose of this study isto examine whether these genes’ polymorphisms influence the clinical symptoms andcognitive functions in schizophrenia and healthy controls. We tried to reveal theschizophrenic predisposing genes and molecular genetic mechanism of influencingthe clinical symoptoms and cognitive functions in schizophrenia.
Methods
A total of350first-episode schizophrenic patients (FEP), and567chronicschizphirenic patients (CSP) and421healthy controls were recruited. Patients withschizophrenia were recruited from the inpatient unit in Beijing Huilongguan hospitaland the control subjects were recruited from the local community. All subjects areHan Chinese and patients with schizophrenia were diagnosed according to ICD-10and CCMD-II-R.
All the subjects signed informed consent and peripheral blood samples werethen taken from them. Genomic DNA was extracted from the whole blood sampleusing a DNA extraction kit (Promega, USA). The DBH rs141116007and ACE rs4340were genotyped using PCR-AFLP technology. We genotyped11polymorphic SNPson the other10genes (rs4360, rs1800497, rs3829787, rs1800872, rs1946518,rs689466, rs5275, rs2958182, rs2239050, rs1801133and rs748806) using SequenomMassArray technology.
The Hardy-Weinberg equilibrium (HWE) for genotypic distributions, theassociations between all candidate SNPs and schizophrenia, the LD between pairsSNPs and haplotype were tested using the online genetic SHEsis soft. The gene-geneinteraction was tested using the MDR soft. The associations between all SNPs andthese clinical features including clinical symptoms and cognitive functions wereperformed with SPSS17.0soft.
Results
1, H-W equilibrium test and LD analysis
(1) H-W equilibrium test
The genotypic distributions of these3SNPs (rs4340, rs3829787and rs5275)were not in HWE in FEP (all, P<0.05), and the genotypic distributions of these3SNPs (rs1800497, rs3829787and rs1801133) were not in HWE of CSP (both, P<0.05),suggesting these SNPs could be the schizophrenic susceptible SNPs or could be inclose linkaged to the schizophrenic susceptible SNPs. The genotypic distributions ofall other SNPs were in HWE in FEP (all, P>0.05), CSP (all, P>0.05) and healthycontrols (all, P>0.05). Thus this sample pool was suitable for the analysis.
(2) LD analysis
The estimated LD showed that rs689466-rs5275was in a LD block.
2, Analysis of case-control
(1) Single SNP analysis of FEP-control
The rs141116007and rs5275were associated with FEP. There were thesignificant differences in the allelic and genotypic frequencies between FEP and healthy controls (all, P<0.05).The rs2239050and rs3829787could be also associationwith FEP. There were the significant differences in the rs2239050allelic andrs3829787genotypic frequencies between FEP and healthy controls (both, P<0.05).
(2) Single SNP analysis of CSP-control
The rs4340、rs18001133and rs748806were associated with CSP. There werethe significant differences in the allelic and genotypic frequencies between CSP andhealthy controls (all, P<0.05). The association could be also showed betweenrs1800497and CSP. There was only a significant difference in the genotypicfrequency between CSP and healthy controls (P<0.05).
(3) Haplotype analysis of case-control
The conditional test was usd to measure the combined effect of2SNPs onCOX-2. In the study of FEP-control, we found that rs689466(C)-rs5275(A)combination as the protective haplotype was associated with FEP (P<0.05).
3, The association between SNPs and clinical symptoms in schizophrenia
(1) The association between SNPs and clinical symptoms in FEP
The rs141116007on DBH and rs1956518on IL-18were associated withpositive sysptoms and total score of clinical symptoms in FEP (all, P<0.05). Thers4340on ACE was associated with negative sysptoms in FEP (P<0.05).
(2) The association between SNPs and clinical symptoms in CSP
The rs689466and rs5275on COX-2were associated with positive sysptoms inCSP (both, P<0.05). The rs2958182on TCF4was associated with negative sysptomsin CSP (P<0.05). The rs1956518on IL-18was associated with total score of clinicalsymptoms in CSP (P<0.05).
4, The association between SNPs and cognitive functions
(1) The association between SNPs and cognitive functions in healthy controls
The rs2958182on TCF4and rs2239050on CACNA1C were associated withattention in healthy controls (both, P<0.05). The rs5257on COX-2was associatedwith language in healthy controls (P<0.05). The rs2958182on TCF4was associatedwith delayed memory and total score of cognition in healthy controls (both, P<0.05).
(2) The association between SNPs and cognitive functions in FEP
The rs141116007on DBH, rs1800497on DRD2and rs5275on COX-2wereassociated with immediate memmory in FEP (all, P<0.05). The rs689466and rs5257on COX-2were associated with language in FEP (both, P<0.05).
(3) The association between SNPs and cognitive functions in CSP
The rs18001133on MTHFR and rs1800872on IL-10were associated withattention in CSP (both, P<0.05). The rs2958182on TCF4and rs18001133on MTHFRwere associated with language in CSP (both, P<0.05). The rs1800497on DRD2andrs2958182on TCF4were associated with delayed memmory in CSP (both,P<0.05).The rs2958182on TCF4was associated with total score of cognitivefunctions in CSP (P<0.05).
Conclusions
Above all, it can be concluded that (1) the genetic polymorphisms of the DBH，COX-2, CHRNA5and CACNA1C genes are likely to confer susceptibility to FEP;(2)the genetic polymorphisms of the ACE，DRD2, MTHFR and GNB1L genes are likelyto confer susceptibility to CSP;（3）The DBH and IL-18genetic variation in FEP andCOX-2genetic variation in CSP influence positive clinical sympotoms;(4) The ACEgenetic variation in FEP and COX-2genetic variation in CSP influence negaitiveclinical sympotoms;(5) The DBH and IL-18genetic variation in FEP and IL-18genetic variation in CSP influence total score of clinical sympotoms;(6) TCF4,CACNA1C and COX-2genetic variations are association cognitive functions inhealthy controls;(7) DBH, DRD2and COX-2genetic variations are associationcognitive functions in FEP;(8) MTHFR, IL-10, DRD2and TCF4genetic variationsare association cognitive functions in CSP;(9) There are genetic and clinicalheterogeneous in schizophrenia.
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