摘要
精神分裂症是最常见、最严重的精神疾患,疾病负担沉重,其病因及发病机制目前尚不清楚。大量的研究发现遗传因素在精神分裂症的发病中具有重要的作用,但至今尚未发现引起精神分裂症发生的特定易感基因。
目的
利用分子生物学技术、遗传流行病学和生物统计学等方法,探讨MBD家族基因多态性与精神分裂症的关联,分析基因-基因交互作用对精神分裂症的影响。本研究所获得的结果将为阐明精神分裂症的遗传规律提供技术支持,为更进一步了解表观遗传机制在精神分裂症发病过程的作用提供证据支持。
方法
本研究以200个中国北方汉族精神分裂症患者及其健康父母组成的核心家系为研究对象,利用生物信息学方法在MBD基因家族上选择10个tag SNPs位点,包括MBD1基因上的4个tag SNPs分别为rs125555、rs140689、rs140687和rs140686,MBD2基因上的3个tag SNPs分别为rs3786254、rs7614和rs1145317,MBD3基因上的3个tag SNPs分别为rs7252741、rs4807934和rs4807122。利用聚合酶链式反应一连接酶检测反应(PCR-LDR)方法检测个体基因型。检验每个位点的基因型频数分布是否符合Hardy-Weinberg平衡；应用基于家系的关联分析方法HHRR和TDT分析单个位点与精神分裂症的关系；应用PBAT软件分析进行多位点联合分析和两个位点之间连锁不平衡程度(LD)分析；应用,检验分析MBD家族基因上的tagSNPs标记位点与精神分裂症临床症状和临床亚组的关联性,证实临床异质性与遗传异质性的存在；应用PGMDR软件进行基因-基因交互作用与精神分裂症的关联分析。
结果
(1)Hardy-Weinberg平衡检验
MIBD1-3基因上的每个标签SNP位点的基因型在健康父母组和患者组中的分布均符合Hardy-Weinberg平衡,说明所选择的位点均可以作为遗传标记进行MBD家族基因多态性与精神分裂症的关联性研究。
(2)HHRR分析
在总体样本中,MBD2基因上rs1145317位点等位基因在父母组和患者组中的频数分布差异有统计学意义(χ2=5.348,P=0.021),表明rs1145317位点与精神分裂症相关联。
在男性患者组中,MBD2基因上的三个位点rs1145317、rs7614和rs3786254位点等位基因在父母组和患者组中的频数分布差异均有统计学意义(χ2=7.400,P=0.007；χ2=4.723,P=0.030；χ2=4.247,P=0.039),表明MBD2基因上的三个位点与男性精神分裂症相关联。
在女性患者组中,MBD3基因上rs4807934位点等位基因在父母组和患者组中的频数分布差异有统计学意义(χ2=4.832,P=0.028),表明rs4807934位点与女性精神分裂症相关联。
(3)TDT分析
在总体样本中,MBD2基因上rs1145317位点传递给患病子女的两个不同等位基因概率偏离了50% (χ2=4.928,P=0.026),G等位基因过多传递给了患者,表明rs1145317位点与精神分裂症相关联。在男性患者组中,MBD2基因上rs1145317、rs7614和rs3786254位点传递给患病子女的两个不同等位基因概率均偏离了50%(χ2=6.420,P=0.011；χ2=4.853,P=0.028；χ2=4.033,P=0.045),rs1145317位点G等位基因过多传递,rs7614位点A等位基因过多传递,rs3786254位点G等位基因过多传递。表明MBD2基因上的三个位点rs1145317、rs7614和rs3786254位点与男性精神分裂症相关联。
在女性患者组中,MBD3基因上rs4807934位点传递给患病子女的两个不同等位基因概率也偏离了50%(χ2=4.378,P=0.036),杂合子父母双亲传递给患病子女的C等位基因过多,表明rs4807934位点与女性精神分裂症相关联。
(4)多位点联合分析结果
MBD1基因上的4个tag SNPs组成的6种单倍体型在患者组和父母组中的分布差异均无统计学意义(P>0.05),提示这些单倍体型与精神分裂症无关联；MBD2基因上的3个tag SNPs组成的3种单倍体型中,rs3786254-rs7614和rs3786254-rs7614-rs1145317单倍体型在患者组和父母组中的分布差异均无统计学意义(P>0.05),提示这些单倍体型与精神分裂症无关联。rs7614-rs1145317单倍体型在患者组和父母组中的分布差异存有统计学意义(P=0.029),提示rs7614-rs1145317组成的单倍体型与精神分裂症相关联；MBD3基因上的3个tagSNPs组成的3种单倍体型在患者组和父母组中的分布差异均无统计学意义(P>0.05),提示这些单倍体型与精神分裂症无关联。
(5)基因-基因交互作用分析结果
PGMDR方法获得rs4087122/rs4807934为多因子基因-基因交互的最佳模型。同时携带rs4807122CC和rs4807934AA基因型的个体以及同时携带rs4807122CT和rs4807934AG基因型的个体罹患精神分裂症的风险增加,相对于rs4807122TT和rs4807934GG基因型的个体风险分别增加了2.114和2.553倍(95%CI：1.125-3.971,P<0.05；95%CI：1.071-6.085,P<0.05)。
(6)临床症状关联分析结果
在总体样本中,MBD1基因上rs140687和rs140689位点与精神分裂症的阳性症状相关联；MBD2基因上rs1145317和rs3786254位点与精神分裂症的阳性症状相关联；MBD3基因上rs7252741、rs4807934和rs4807122位点与精神分裂症的阳性症状相关联。
在男性患者组中,MBD1基因上rs125555、rs140686和rs140687位点与精神分裂症的阳性症状相关联；MBD2基因上rs7614、rs1145317和rs3786254位点与精神分裂症的阳性症状相关联；MBD3基因上rs7252741和rs4807934位点与精神分裂症的阳性症状相关联；MBD2基因上rs1145317位点与精神分裂症的病前人格相关联。
在女性患者组中, MBD1基因上rs140686、rs140689和rs125555位点与精神分裂症的阳性症状相关联；MBD2基因上rs7614、rs3786254和rs1145317位点与精神分裂症的阳性症状相关联；MBD3基因上rs4807122和rs7252741位点与精神分裂症的阳性症状相关联。
(7)临床亚型关联分析结果
在总体样本中,MBD1和MBD2基因上各位点与偏执型和未分型精神分裂症无关联；MBD3基因rs7252741位点与偏执型精神分裂症相关联；MBD3基因各位点与未分型精神分裂症无关联。
在男性患者组中,MBD2基因上rs1145317位点和rs3786254位点与男性偏执型精神分裂症相关联；MBD3基因上rs7252741位点与男性偏执型精神分裂症相关联。在女性患者组中,MBD2基因上rs7614与女性未分型精神分裂症相关联；MBD3基因上rs4807122位点与女性未分型精神分裂症相关联。
结论
由上述分析结果,可以得到如下结论：①MBD2(rs1145317)基因位点与精神分裂症相关联；②MBD2(rs1145317、rs7614、rs3786254)基因位点与男性精神分裂症相关联；MBD3(rs4807934)基因位点与女性精神分裂症相关联；③MBD2基因rs7614位点和rs1145317位点组成的单倍型(rs7614-rs1145317)与精神分裂症相关联；④基因-基因交互作用研究发现,同时携带rs4807122CC和rs4807934AA基因型的个体以及同时携带4807122CT和rs4807934AG基因型的个体罹患精神分裂症的风险增加；⑤MBD1、MBD2、MBD3基因中存在多个与精神分裂症临床症状相关联的位点,女性精神分裂症患者的钟情妄想、怪异行为、情感淡漠和其他妄想症状表现多于男性；⑥MBD2、MBD3基因中存在多个与精神分裂症临床亚型相关联的位点；⑦精神分裂症MBD基因的遗传存在性别差异,证实精神分裂症存在临床异质性和遗传异质性。
综上所述,本研究结果证明了MBD基因家族可能与精神分裂症发病相关。不同位点间的相互作用与精神分裂症相关联,有力地支持了复杂疾病的多基因学说,同时证实了精神分裂症的临床异质性和遗传异质性。
Association study between schizophrenia and gene polymorphisms of methyl-CpG-binding protein family
Schizophrenia is the most common and serious mental disease, the burden of disease is very heavy. Until now, the pathogenesis of schizophrenia remains unknown. Most studies found that genetic factor may be played a major role in schizophrenia. The specific susceptibility genes associated with schizophrenia remains unidentified.
Objective
The purpose of this study is to identify the genetic association between the polymorphisms of methyl-CpG-binding protein (MBD) family genes and schizophrenia by using the protocols in molecular biology, genetic epidemiology and biostatistics, and to analyze the effect of gene-gene interaction. The results obtained in this study will provide technical support to clarify the inheritance of schizophrenia, and provide supporting evidence to understand the role of epigenetic mechanisms in the pathogenesis of schizophrenia.
Methods
200 family trios consisted of father, mother, and affected offspring with schizophrenia were collected for MBD genetic analysis.10 tag SNPs were chosen on MBD family genes including rs125555、rs140689, rs140687 and rs140686 on MBD1 gene, rs3786254、rs7614 and rs1145317 on MBD2 gene, rs7252741, rs4807934 and rs4807122 on MBD3 gene. Ten tag SNPs were genotyped using PCR-based ligase detection reaction analysis. The genotype frequency of each tag SNPs distribution was tested for Hardy-Weinberg equilibrium. The HHRR test and TDT test were used to detect the allelic association between tag SNPs of MBD gene and schizophrenia. Haplotype analysis and Linkage disequilibrium analysis was using Pedigree based association test (PBAT) software. The association between tag SNPs of MBD genes and clinical symptoms and type of schizophrenia was used byχ2 test. To elucidate the clinical heterogeneity and genetic heterogeneity based on clinical subgroups analyzed. The relationship between gene-gene interaction and schizophrenia was analyzed by Pedigree-based generalized multifactor dimensionality reduction (PGMDR) software.
Results
(1)H-W test
The genotype frequency distributions of each tag SNPs in patient group and parent group were not deviated from the H-W equilibrium, thus each SNP could used as genetic markers to test the relationship between MBD genes and schizophrenia.
(2) HHRR test
In total samples, HHRR test showed that MBD2 gene rs1145317 allele frequency distribution was statistically significant difference in case and control group (χ2= 5.348, P=0.021). This result indicates that the rs1145317 locus associated with schizophrenia.
In the male patient group, MBD2 gene of rs1145317, rs7614 and rs3786254 allele frequency distribution were statistically significant difference in case and control group (χ2=7.400, P=0.007;χ2=4.723, P=0.030;χ2= 4.247, P=0.039), show that the MBD2 gene of rs1145317. rs7614 and rs3786254 associated with schizophrenia in the male patients group.
In the female patient group. MBD3 gene rs4807934 allele was statistically significant difference in case and control group (χ2= 4.832. P= 0.028). show that the rs4807934 locus associated with schizophrenia in the female patients group.
(3) TDT test
In total samples, TDT analysis showed that the probability of the two different alleles in MBD2 gene rs1145317 deviated from 50% from heterozygous parents (P<0.05). G-allele was passed too much to the patient. This result indicates that the rs1145317 locus associated with schizophrenia.
In the male patient group, the probability of the two different alleles in MBD2 gene rs1145317, rs7614 and rs3786254 deviated from 50% from heterozygous parents (χ2=6.420,P=0.011;χ2=4.853,P=0.028:χ2=4.033,P=0.045). G-allele on rs1145317 was passed too much to the patient. A-allele on rs7614 was passed too much to the patient. G-allele on rs3786254 was passed too much to the patient. This result indicates that the rs1145317. rs7614 and rs3786254 locus associated with schizophrenia in the male patients group.
In the female patient group, the probability of the two different alleles in MBD3 gene rs4807934 deviated from 50% from heterozygous parents (χ2=4.378,P=0.036). C-allele on rs4807934 was passed too much to the patient. This result indicates that the rs4807934 locus associated with schizophrenia in the female patients group.
(4) Haplotype test
There was no haplotypic association for the six haplotype system in the MBD1 gene. There was no haplotypic association for the haplotype system of rs3786254-rs7614 and rs3786254-rs7614-rs1145317 in the MBD2 gene. There was no haplotypic association for the three haplotype system in the MBD3 gene. The result indicates that these haplotype system were not associated with schizophrenia. The haplotype system of rs7614-rs 1145317 frequency distribution were statistically significant difference in case and control group (P=0.029). This result indicates that the haplotype system of rs7614-rs1145317 associated with schizophrenia.
(5) Analysis for gene-gene interaction
The PGMDR method identified that the best model of rs4087122/rs4807934 to analyze the gene-gene interaction of schizophrenia. Person who carries rs4807122CC or rs4807934AA genotypes and rs4807122CT or rs4807934AG genotypes of MBD3 gene at the same time will have more risk to affect the disease. The risks were 2.114 and 2.553 times respectively compared to the person who carries rs4807122TT genotype and rs4807934GG genotype (95%CI:1.125-3.971, P<0.05 95%CI:1.071～6.085, P<0.05).
(6) Analysis for clinical symptoms
In total samples, rs140687 and rs140689 on MBD1 gene; rs1145317 and on MBD2 gene; rs7252741, rs4807934 and rs4807122 on MBD3 gene were associated with some positive symptoms of schizophrenia.
In the male patient group, rs125555、rs140686 and rs140687 on MBD1 gene; rs7614, rs1145317 and rs3786254 on MBD2 gene; rs7252741 and rs4807934 on MBD3 gene were associated with some positive symptoms of schizophrenia. The rs1145317 on MBD2 gene was associated with premorbid personality of schizophrenia.
In the female patient group, rs140686、rs140689 and rsl25555 on MBD1 gene; rs7614、rs3786254 and rs1145317 on MBD2 gene; rs4807122 and rs7252741 on MBD3 gene were associated with some positive symptoms of schizophrenia.
(7) Analysis for clinical type
In total samples, the tag SNPs of MBD1 and MBD2 gene were not associated with paranoid and undifferentiated schizophrenia. The rs7252741 of MBD3 gene was associated with paranoid schizophrenia. The tag SNPs of MBD3 gene were not associated with undifferentiated schizophrenia.
In the male patient group, the rs1145317 and rs3786254 of MBD2 gene were associated with male paranoid schizophrenia. The rs7252741 of MBD2 gene was associated with male paranoid schizophrenia.
In the female patient group, the rs4807122 of MBD3 gene was associated with female undifferentiated schizophrenia.
Conclusions
According to the results, we have obtain the following conclusions:①MBD2 gene rs1145317 locus was associated with schizophrenia;②rs1145317、rs7614、rs3786254 loci of MBD2 gene were associated with male schizophrenia; MBD3 gene rs48079334 locus was associated with female schizophrenia;③The haplotype system of rs7614-rsl 145317 associated with schizophrenia;④The best model to analyze the gene-gene interaction of schizophrenia was rs4087122/rs4807934. Person who carries rs4807122CC or rs4807934AA genotypes and rs4807122CT or rs4807934AG genotypes of MBD3 gene at the same time will have more risk to affect the disease;⑤There are many SNPs in the MBD genes, which associate with the schizophrenic clinical symptoms. The female schizophrenia has more symptoms of delusion of being loved, bizarre behavior, affective flattening and other delusions;⑥There are many SNPs in the MBD2 and MBD3 gene, which associate with the schizophrenic clinical types;⑦We found the genetic of MBD gene in schizophrenia has gender difference, and the inheritance of schizophrenia has clinical heterogeneity and genetic heterogeneity.
In sum, we found the MBD genes were associated with schizophrenia. The results support the polygenic theory of complex disease. At the same time, these results prove that schizophrenia has the clinical heterogeneity and genetic heterogeneity.
引文
[1]CARPENTER WT JR., BUCHANAN RW. Schizophrenia[J]. New Engl J Med, 1994,330(10):681-690.
[2]PALHA AP, ESTEVES MF. The origin of dementia praecox[J]. Schizophr Res,1997,28(2-3):99-103.
[3]STOTZ-INGENLATH G. Epistemological aspects of Eugen Bleuler's conception of schizophrenia in 1911[J]. Med Health Care Philos,2000, 3(2):153-159.
[4]JABLENSKY A. The 100-year epidemiology of schizophrenia [J]. Schizophr Res,1997,28(2-3):111-125.
[5]EATON WW. Update on the epidemiology of schizophrenia[J]. Epidemiologic reviews,1991,13:320-328.
[6]EATON W. Evidence for universality and uniformity of schizophrenia around the world:assessment and implications[J]. In Search for the Causes of Schizophrenia, Vol. IV:Balance of the Century. Berlin:Springer-Verlag,1999, 21-33.
[7]沈渔邨，陈昌惠,张维熙.国内12地区精神疾病流行学调查的方法学及资料分析[J].中华神经精神科杂志,1986，19(1)：65-69.
[8]陈昌惠,沈渔,席廷铭,等.精神分裂症的发病率和患病率[J].中华神经精神科杂志,1984,17(5)：321-324.
[9]WIDERLOV B, LINDSTROM E, VON KNORRING L. One-year prevalence of long-term functional psychosis in three different areas of Uppsala[J]. Acta Psychiatr Scand,1997,96(6):452-458.
[10]NIELSEN J, NIELSEN JA. A census study of mental illness in Samso[J]. Psychological Medicine,1977,7(3):491-503.
[11]DE SAL VIA D, BARBATO A, SALVO P, et al. Prevalence and incidence of schizophrenic disorders in Portogruaro. An Italian case register study[J]. J Nerv Ment Dis,1993,181(5):275-282.
[12]HWU HG, FARAONE SV, LIU CM, et al. Taiwan schizophrenia linkage study:the field study[J]. Am J Med Genet B Neuropsychiatr Genet,2005, 134(1):30-36.
[13]LEE CK. A nationwide epidemiological study of mental disorders in Korea[J]. Psychiatry Clin Neurosci,1998,52 Suppl:268-274.
[14]PHANTHUNANE P. VOS T, WHITEFORD H. et al. Schizophrenia in Thailand:prevalence and burden of disease[J]. Popul Health Metr,2010.8(1): 24.
[15]MURPHY HB, TAUMOEPEAU BM. Traditionalism and mental health in the South Pacific:a re-examination of an old hypothesis [J]. Psychol Med,1980. 10(3):471-482.
[16]ZIMMERMANN-TANSELLA C, BURTI L, FACCINCANI C. et al. Bringing into action the psychiatric reform in South-Verona. A five year experience[J]. Acta Psychiatr Scand,1985.71(S316):71-86.
[17]CHEUNG P, WILDER-SMITH E. Anorexia nervosa and schizophrenia in a male Chinese[J]. Int J Eat Disord,1995,18(1):103-106.
[18]BABIGIAN HM, ODOROFF CL. The mortality experience of a population with psychiatric illness[J]. Am J Psychiatry.1969,126(4):470-480.
[19]BEN-TOVIM DI, CUSHNIE JM. The prevalence of schizophrenia in a remote area ofBotswana[J].Br J Psychiatry,1986,148:576-580.
[20]HALLDIN, J. Prevalence of mental disorder in an urban population in central Sweden in relation to social class, marital status and immigration[J]. Acta Psychiatr Scand.1985,71(2):117-127.
[21]Freeman H, Alpert M. Prevalence of schizophrenia in an urban population[J]. Br J Psychiatry.1986,149:603-611.
[22]WING JK, BABOR T, BRUGHA T, et al. SCAN:Schedules for Clinical Assessment in Neuropsychiatry[J]. Arch Gen Psychiatry.1990,47(6):589-593.
[23]BAMRAH JS. FREEMAN HL. GOLDBERG DP, et al. Epidemiology of schizophrenia in Salford.1974-84. Changes in an urban community over ten years[J]. Br J Psychiatry.1991.159:802-810.
[24]BURNAM MA, HOUGH RL, ESCOBAR JI, et al. Six-month prevalence of specific psychiatric disorders among Mexican Americans and non-Hispanic whites in Los Angeles[J]. Arch Gen Psychiatry,1987,44(8):687-694.
[25]BLAZER D, GEORGE LK, LANDERMAN R, et al. Psychiatric disorders. A rural/urban comparison[J]. Arch Gen Psychiatry,1985,42(7):651-656.
[26]MYERS JK, WEISSMAN MM, TISCHLER GL, et al. Six-month prevalence of psychiatric disorders in three communities 1980 to 1982[J]. Arch Gen Psychiatry,1984,41(10):959-967.
[27]CANINO GJ, BIRD HR, SHROUT PE, et al. The Spanish Diagnostic Interview Schedule. Reliability and concordance with clinical diagnoses in Puerto Rico[J]. Arch Gen Psychiatry.1987,44(8):720-726.
[28]SIKANARTEY T, EATON WW. Prevalence of schizophrenia in the Labadi District of Ghana[J]. Acta Psychiatr Scand,1984,69(2):156-161.
[29]LEHTINEN V. The epidemiology of schizophrenia[J]. Nord Med,1987, 102(4):112-126.
[30]NANDI DN, BANERJEE G, BORAL GC, et al. Socio-economic status and prevalence of mental disorders in certain rural communities in India[J]. Acta Psychiatr Scand,1979,59(3):276-293.
[31]DILLING H, WEYERER S. Prevalence of mental disorders in the small-town--rural region of Traunstein (Upper Bavaria)[J]. Acta Psychiatr Scand,1984,69(1):60-79.
[32]WEISSMAN MM, MYERS JK, HARDING PS. Psychiatric disorders in a U.S. urban community:1975-1976[J]. Am J Psychiatry,1978,135(4):459-462.
[33]张维熙,沈渔邨，李淑然,等.中国七个地区精神疾病流行病学调查[J].中华精神科杂志,1998,5(1)：69-71.
[34]VAZQUEZ BARQUERO JL, MUNOX PE, MADOZ JAUREGUI V, et al. The influence of the process of urbanization on the prevalence of neurosis. A community survey [J]. Acta Psychiatr Scand,1982,65(3):161-170.
[35]HODIAMONT P. PEER N. SYBERN N. Epidemiological aspects of psychiatric disorder in a Dutch health area[J]. Psychol Med.1987.17(2): 495-505.
[36]WALSH D. Coeliac Disease and Schizophrenia[J]. Br Med J,1973, 2(5860):242.
[37]WALSH D. The treated prevalence of mental illness in the Republic of Ireland: the three county case register study[J]. Psychol Med,1980,10(3):465-70.
[38]BEBBINGTON PE, HURRY J, TENNANT C. Psychiatric disorders in selected immigrant groups in Camberwell[J]. Social Psychiatry,1981,16(1): 43-51.
[39]MAVREAS V, BEBBINGTON P, DER G. The structure and validity of acculturation. Analysis of an acculturation scale[J]. Soc Psychiatry Psychiatr Epidemiol,1989,24(5):233-40.
[40]ALEMAN A. KAHN RS, SELTEN JP. Sex differences in the risk of schizophrenia:evidence from meta-analysis[J]. Arch Gen Psychiatry,2003, 60(6):565-571.
[41]FARRIS R, DUNHAM H. Mental disorders in urban areas[M]. Chicago: Chicago University Press.1939.
[42]张继志.精神医学与心理卫生研究[M].北京：北京出版社.1994.
[43]万纯，付美珍，兰胜作，等.江西省宜春市精神分裂症患病率的调查结果[J].四川精神卫生,2002.15(3)：178-179.
[44]王世纪，郭翠玲,郭虹,等.安徽阜阳市精神分裂症流行病学调查(1984-1994)[J].临床精神医学,2002，12(1)：3-4.
[45]EATON WW. Epidemiology of schizophrenia[J]. Epidemiologic Reviews, 1985.7(1):105-126.
[46]BRESNAHAN M, MENEZES P, VARMA V, et al. Geographical variation in incidence, course and outcome of schizophrenia:a comparison of developing and developed countries. In The epidemiology of schizophrenia [M]. Cambridge University Press,2003.
[47]TORREY EF. MILLER J. RAWLINGS R. et al. Seasonality of births in schizophrenia and bipolar disorder:a review of the literature [J]. Schizophr Res. 1997.28(1):1-38.
[48]KINNEY DK, JACOBSEN B, JANSSON L. Winter birth and biological family history in adopted schizophrenics[J]. Schizophr Res,2000,44(2): 95-103.
[49]DAVIES G, WELHAM J, CHANT D, et al. A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia[J]. Schizophrenia bulletin,2003,29(3):587-593.
[50]SMESNY S, ROSBURG T, KLEMM S, et al. The influence of age and gender on niacin skin test results-implications for the use as a biochemical marker in schizophrenia[J]. J Psychiatr Res,2004,38(5):537-543.
[51]NADALIN S, BURETIC-TOMLJANOVIC A, RUBES A, G, et al. Niacin skin flush test:a research tool for studying schizophrenia[J]. Psychiatr Danub,2010, 22(1):14-27.
[52]MCGORRY PD, NELSON B, GOLDSTONE S, et al. Clinical staging:a heuristic and practical strategy for new research and better health and social outcomes for psychotic and related mood disorders[J]. Can J Psychiatry,2010, 55(8):486-497.
[53]CROW TJ. Positive and negative schizophrenic symptoms and the role of dopamine[J]. Br J Psychiatry,1980,137(4):383-386.
[54]World Health Organization. The World Health Report 1999. Geneva:WHO, 1999,78.
[55]GARATTINI L, BARBUI C, CLEMENTE R. et al. Direct costs of schizophrenia and related disorders in Italian community mental health services:a multicenter, prospective 1-year follow-up study[J]. Schizophr Bull, 2004,30(2):295.
[56]韩柏.精神分裂症患的现代研究[M].第1版.北京：中国科学技术出版社，2003，1.
[57]LINCOLN TM, HODGINS S. Is lack of insight associated with physically aggressive behavior among people with schizophrenia living in the community?[J]. Nerv Ment Dis,2008.196(1):62-66.
[58]TSUANG MT. KENDLER KK. GRUENBERG AM. DSM-Ⅲ schizophrenia: is there evidence for familial transmission[J]. Acta Psychiatr Scand Suppl, 1985,319(71):77-83.
[59]HARRISON PJ, OWEN MJ. Gene for schizophrenia? Resent findings and their pathophysiological Implications[J]. Lancet,2003,361(9355):417-419.
[60]BARON M. Genetic models of schizophrenia. Acta Psychiatr Scand,1982, 65(4):263-275.
[61]GOTTESMAN II. Schizophrenia Genesis:The Origin of Madness[M]. New York:Freeman.1991.
[62]TIENARI, P. Interaction between genetic vulnerability and family environment:the Finnish adoptive family study of schizophrenia[J]. Acta Psychiatr Scand,1991,84(5):460-465.
[63]HESTON, LL. Psychiatric disorders in foster home reared children of schizophrenic mothers[J]. Br J Psychiatry,1966.112(489):819-825.
[64]KARLSSON H, BACHMANN S, SCHRODER J, et al. Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia[J]. Proc Natl Acad Sci USA,2001,98(8):4634-4639.
[65]SELTEN JP, FRISSEN A, LENSVELT-MULDERS G. et al. Schizophrenia and 1957 pandemic of influenza:meta-analysis[J]. Schizophr Bull,2010.36(2): 219-228.
[66]GOODMAN, R. Obstetric complications and schizophrenia[J]. Br J Psychiatry, 1988,153(6):850.
[67]ST CLAIR D. XU M, WANG P. et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961 [J]. Jama,2005,294(5): 557-562.
[68]吴福喜，黎丽燕，朱海兵.等.精神分裂症患者父母教养方式特征[.J].中国临床康复,2005，9(20)：42-43.
[69]HUDSON C G. Socioeconomic status and mental illness:tests of the social causation and selection hypotheses [J]. Am J psychiatry.2005.75(1):3-18.
[70]PICKER M. LEIBOLD L. ENDSLEY B, et al. Modulation of the behavioral effects of anticonvulsant druas by an external discriminative stimulus in the pigeon[J]. J Pharmacol Exp Ther,1986,238(2):529-535.
[71]BOWERS MB., JR. Central dopamine turnover in schizophrenic syndromes [J]. Arch Gen Psychiatry,1974,31(1):50-54.
[72]CROW TJ, JOHNSTONE EC, DEAKIN JF, et al. Dopamine and schizophrenia[J]. Lancet,1976,2(7985):563-566.
[73]LIEBERMAN JA, KANE JM, SARANTAKOS S, et al. Prediction of relapse in schizophrenia[J]. Arch Gen Psychiatry,1987,44(7):597-603.
[74]CROW TJ. A re-evaluation of the viral hypothesis:is psychosis the result of retroviral integration at a site close to the cerebral dominance gene?[J]. Br J Psychiatry,1984,145:243-253.
[75]CRAWLEY JC, OWENS DG, CROW TJ, et al. Dopamine D2 receptors in schizophrenia studied in vivo[J]. Lancet,1986,2(8500):224-225.
[76]THEBERGE J, AL-SEMAAN Y. WILLIAMSON PC, et al. Glutamate and glutamine in the anterior cingulate and thalamus of medicated patients with chronic schizophrenia and healthy comparison subjects measured with 4.0-T proton MRS[J]. Am J Psychiatry,2003,160(12):2231-2233.
[77]GLUCK MR, THOMAS RG, DAVIS KL, et al. Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients [J]. Am J Psychiatry,2002,159(7):1165-1173.
[78]KESSLER RM, WOODWARD ND, RICCARDI P, et al. Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects[J]. Biol Psychiatry.2009,65(12):1024-1031.
[79]ROTMAN A, SHATZ A, SZEKELY GA. Correlation between serotonin uptake and imipramine binding in schizophrenic patients [J]. Prog Neuropsychopharmacol Biol Psychiatry,1982,6(1):57-61.
[80]OWEN F, SIMPSON M. The neurochemistry of schizophrenia[J]. Mol Cell Biol Hum Dis Ser,1994,4:133-159.
[81]ROBERTS E. Prospects for research on schizophrenia. An hypotheses suggesting that there is a defect in the GABA system in schizophrenia[J]. Neurosci Res Program Bull,1972,10(4):468-482.
[82]REYNOLDS GP, PEARSON SJ. Brain GABA levels in asymptomatic Huntington's disease[J]. N Engl J Med,1990,323(10):682.
[83]KEMALI D, DEL VECCHIO M, MAJ, M. Increased noradrenaline levels in CSF and plasma of schizophrenic patients[J]. Biol Psychiatry,1982,17(6): 711-717.
[84]DAJAS F, BARBEITO L, MARTINEZ-PESQUERA G, et al. Plasma noradrenaline and clinical psychopathology in schizophrenia. A correlation analysis[J]. Neuropsychobiology,1983,10(2-3):70-74.
[85]MCNEIL TF, CANTOR-GRAAE E, WEINBERGER DR. Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia[J]. Am J Psychiatry,2000, 157(2):203-212.
[86]NOPOULOS PC, CEILLEY JW. GAILIS EA. et al. An MRI study of cerebellar vermis morphology in patients with schizophrenia:evidence in support of the cognitive dysmetria concept[J]. Biol Psychiatry,1999.46(5): 703-711.
[87]THOMPSON PM. VIDAL C. GIEDD JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia[J]. Proc Natl Acad Sci USA.2001,98(20): 11650-11655.
[88]VAN KAMMEN DP. YAO JK. GOETZ. K. Polyunsaturated fatty acids, prostaglandins, and schizophrenia[J]. Ann N Y Acad Sci,1989.559:411-423.
[89]SHEN Q, LI ZQ, SUN Y. The role of pro-inflammatory factors in mediating the effects on the fetus of prenatal undernutrition:implications for schizophrenia[J]. Schizophr Res,2008,99(1-3):48-55.
[90]NOEVA K, MANOLOVA Z. Antigamma globulin factors and IgG. IgA and IgM levels in schizophrenia, manic-depressive psychosis and disseminated sclerosis patients[J]. Acta Microbiol Virol Immunol (Sofiia),1976,4:105-112.
[91]WANG C, JIAN BX. JIANG XD. et al. Investigation of allotypes of HLA class III (C2. BF and C4) in patients with schizophrenia[J]. Chin Med J (Engl). 1992,105(4):316-318.
[92]DALY MJ, RIOUX JD, SCHAFFNER, SF, et al. High-resolution haplotype structure in the human genome[J]. Nat Genet,2001,29(2):229-232.
[93]JEFFREYS AJ, KAUPPI L, NEUMANN R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex[J]. Nat Genet,2001,29(2):217-222.
[94]PATIL N, NOURI N, MCALLISTER L, et al. Single-nucleotide polymorphism genotyping using microarrays[J]. Curr Protoc Hum Genet,2001, Chapter 2:UNIT 2.9.
[95]RITCHIE MD, HAHN LW, ROODI N, et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer[J]. Am J Hum Genet,2001,69(1):138-147.
[96]LOU XY, CHEN GB, YAN L, et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence [J]. Am J Hum Genet,2007,80(6):1125-1137.
[97]LOU XY, CHEN GB, YAN L, et al. A combinatorial approach to detecting gene-gene and gene-environment interactions in family studies[J]. Am J Hum Genet,2008,83(4):457-467.
[98]ABERG K, SAETRE P, JAREBORG N, et al. Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia[J]. Proc Natl Acad Sci USA,2006,103(19): 7482-7487.
[99]ABERG K, AXELSSON E, SAETRE P, et al. Support for schizophrenia susceptibility locus on chromosome 2q detected in a Swedish isolate using a dense map of microsatellites and SNPs[J]. Am J Med Genet B Neuropsychiatr Genet 2008,147B (7):1238-1244.
[100]AKSENOVA MG, IVANOVA GM, BRAGA EA, et al. Analysis of correlation between presence of satellite marker (GATG)n in locus DI3S699 (13q14) and schizophrenia and affective psychoses[J]. Mol Biol (Mosk).1997. 31(6):1112-1115.
[101]AUSTIN CP, HOLDER DJ, MA L, et al. Mapping of hKCa3 to chromosome 1 q21 and investigation of linkage of CAG repeat polymorphism to schizophrenia[J]. Mol Psychiatry,1999,4(3):261-266.
[102]BAILER U, LEISCH F, MESZAROS K, et al. Genome scan for susceptibility loci for schizophrenia[J]. Neuropsychobiology,2000,42(4):175-182.
[103]BLACKWOOD DH, FORDYCE A, WALKER MT, Et al. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome lq42 that directly disrupts brain-expressed genes:clinical and P300 findings in a family[J]. Am J Hum Genet,2001,69(2):428-433.
[104]BLOUIN JL, DOMBROSKI BA, NATH SK, et al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21 [J]. Nat Genet,1998,20(1): 70-73.
[105]BRZUSTOWICZ LM, HODGKINSON KA, CHOW EW, et al. Location of a major susceptibility locus for familial schizophrenia on chromosome lq21-q22[J]. Science,2000.288(5466):678-682.
[106]BRZUSTOWICZ LM, HAYTER JE, HODGKINSON KA. et al. Fine mapping of the schizophrenia susceptibility locus on chromosome lq22[J]. Hum Hered, 2002.54(4):199-209.
[107]BRZUSTOWICZ LM. SIMONE J. MOHSENI P, et al. Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome lq22[J]. Am J Hum Genet,2004,74(5):1057-1063.
[108]BULAYEVA KB, GLATT SJ, BULAYEV OA, et al. Genome-wide linkage scan of schizophrenia:a cross-isolate study [J]. Genomics,2007,89(2): 167-177.
[109]CAMPION D, D'AMATO T, LAKLOU H, et al. Failure to replicate linkage between chromosome 5qll-q13 markers and schizophrenia in 28 families[J]. Psychiatry Res,1992,44(3):171-179.
[110]CHEN Q, HE G, WANG XY. et al. Positive association between synapsin Ⅱ and schizophrenia[J]. Biol Psychiatry.2004.56(3):177-181.
[111]CHEN X. WANG X. HOSSAIN S. et al. Interleukin 3 and schizophrenia:the impact of sex and family history[J]. Mol Psychiatry,2007,12(3):273-282.
[112]CHEN X, WANG X, CHEN Q, et al. MEGF10 association with schizophrenia[J]. Biol Psychiatry,2008,63(5):441-448.
[113]DANIELS JK, SPURLOCK G, WILLIAMS NM, et al. Linkage study of chromosome 6p in sib-pairs with schizophrenia[J]. Am J Med Genet,1997, 74(3):319-323.
[114]DEMIRHAN O, TASTEMIR DC. Chromosome aberrations in a schizophrenia population[J]. Schizophr Res,2003,65(1):1-7.
[115]DECKER HS. The psychiatric works of Emil Kraepelin:a many-faceted story of modern medicine[J]. J Hist Neurosci,2004,13(3):248-276.
[116]EDGAR PF, DOUGLAS JE, COOPER GJ, ET AL. Comparative proteome analysis of the hippocampus implicates chromosome 6q in schizophrenia [J]. Mol Psychiatry,2000,5(1):85-90.
[117]EKELUND J, LICHTERMANN D, HOVATTA I, et al. Genome-wide scan for schizophrenia in the Finnish population:evidence for a locus on chromosome 7q22[J]. Hum Mol Genet,2000,9(7):1049-1057.
[118]EKELUND J, HOVATTA I, PARKER A, et al. Chromosome 1 loci in Finnish schizophrenia families[J]. Hum Mol Genet,2001,10(15):1611-1617.
[119]EKELUND J, HENNAH W, HIEKKALINNA T, et al. Replication of 1q42 linkage in Finnish schizophrenia pedigrees[J]. Mol Psychiatry,2004,9(11): 1037-1041.
[120]ESCAMILLA MA, ONTIVEROS A, NICOLINI H, et al. A genome-wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry [J]. Am J Med Genet B Neuropsychiatr Genet,2007, 144B(2):193-199.
[121]FALLIN MD, LASSETER VK, WOLYNIEC PS. et al. Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22[J]. Am J Hum Genet,2003, 73(3):601-611.
[122]FARAONE SV. HWU HG. LIU CM. et al. Genome scan of Han Chinese schizophrenia families from Taiwan:confirmation of linkage to 10q22.3[J]. Am J Psychiatry,2006,163(10):1760-1766.
[123]FANOUS AH, NEALE MC, WEBB BT, et al. A genome-wide scan for modifier loci in schizophrenia[J]. Am J Med Genet B Neuropsychiatr Genet, 2007,144B (5):589-595.
[124]FLOMEN RH. COLLIE DA. OSBORNE S, et al.Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder[J]. Am J Med Genet B Neuropsychiatr Genet,2006,141B (6):571-575.
[125]FLETCHER JM, EVANS K, BAILLIE D, et al. Schizophrenia-associated chromosome 11q21 translocation:identification of flanking markers and development of chromosome 11q fragment hybrids as cloning and mapping resources [J]. Am J Hum Genet,1993.52(3):478-490.
[126]FREEDMAN R, COON H, MYLES-WORSLEY M, et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus[J]. Proc Natl Acad Sci USA.1997.94(2):587-592.
[127]FREEDMAN R, LEONARD S, GAULT JM, et al. Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7)[J]. Am J Med Genet, 2001.105(1):20-22.
[128]GURLING HM, KALSI G, BRYNJOLFSON J, et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes lq32.2,5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23[J]. Am J Hum Genet,2001.68(3):661-673.
[129]HAMPSON RM. MALLOY MP, MORS O, et al. Mapping studies on a pericentric inversion (18) (pi 1.31 q21.1) in a family with both schizophrenia and learning disability [J]. Psychiatr Genet.1999.9(3):161-163.
[130]HAMSHERE ML. BENNETT P. WILLIAMS N. et al. Genomewide linkage scan in schizoaffective disorder:significant evidence for linkage at lq42 close to DISCI, and suggestive evidence at 22qll and 19p 13[J]. Arch Gen Psychiatry,2005,62(10):1081-1088.
[131]HWU HG, LIU CM, FANN CS, et al. Linkage of schizophrenia with chromosome lq loci in Taiwanese families[J]. Mol Psychiatry,2003,8(4): 445-452.
[132]JONSSON EG, EDMAN-AHLBOM B, SILLEN A, et al. Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia:an association study[J]. Prog Neuropsychopharmacol Biol Psychiatry,2006,30(5):924-933.
[133]KARAYIORGOU M, GOGOS JA. The molecular genetics of the 22q11-associated schizophrenia[J]. Brain Res Mol Brain Res,2004,132(2): 95-104.
[134]KALSI G, MANKOO B, CURTIS D, et al. New DNA markers with increased informativeness show diminished support for a chromosome 5q11-13 schizophrenia susceptibility locus and exclude linkage in two new cohorts of British and Icelandic families[J]. Ann Hum Genet,1999,63(Pt 3):235-247.
[135]KENDLER KS, MYERS JM, O'NEILL FA, et al. Clinical features of schizophrenia and linkage to chromosomes 5q,6p,8p, and 10p in the Irish Study of High-Density Schizophrenia FamiliesfJ]. Am J Psychiatry,2000, 157(3):402-408.
[136]LERER B. SEGMAN RH, HAMDAN A, et al.Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24[J], Mol Psychiatry,2003,8(5): 488-498.
[137]LEONARD S, FREEDMAN R. Genetics of chromosome 15q13-q14 in schizophrenia[J]. Biol Psychiatry,2006,60(2):115-122.
[138]LIEN YJ, LIU CM, FARAONE SV, et al. A genome-wide quantitative trait loci scan of neurocognitive performances in families with schizophrenia[J]. Genes Brain Behav,2010,9(7):695-702.
[139]LIN MW, SHAM, P. HWU HG. et al. Suggestive evidence for linkage of schizophrenia to markers on chromosome 13 in Caucasian but not Oriental populations[J]. Hum Genet,1997,99(3):417-420.
[140]LINDHOLM E, EKHOLM B, BALCIUNIENE J, et al. Linkage analysis of a large Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23[J]. Am J Med Genet,1999,88(4): 369-377.
[141]LINDHOLM E, EKHOLM B, SHAW S, et al. A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees[J]. Am J Hum Genet,2001,69(1):96-105.
[142]LIU YL, FANN CS. LIU CM, et al.RASD2, MYH9, and CACNG2 genes at chromosome 22q12 associated with the subgroup of schizophrenia with non-deficit in sustained attention and executive function[J]. Biol Psychiatry, 2008,64(9):789-796.
[143]MAGRI C, GARDELLA R, BARLATI SD, et al. Glutamate AMPA receptor subunit 1 gene (GRIA1) and DSM-IV-TR schizophrenia:a pilot case-control association study in an Italian sample [J]. Am J Med Genet B Neuropsychiatr Genet,2006,141B(3):287-293.
[144]MAGRI C. SACCHETTI E. TRAVERSA M. et al. New copy number variations in schizophrenia[J]. PLoS One.2010.5(10):e13422.
[145]MAZIADE M. RAYMOND V, CLICHE D. et al. Linkage results on 11Q21-22 in Eastern Quebec pedigrees densely affected by schizophrenia[J]. Am J Med Genet,1995,60(6):522-528.
[146]MAZIADE M, ROY MA, ROUILLARD E, et al. A search for specific and common susceptibility loci for schizophrenia and bipolar disorder:a linkage study in 13 target chromosomes[J]. Mol Psychiatry,2001.6(6):684-693.
[147]MAZIADE M, FOURNIER A. PHANEUF D, et al. Chromosome lq12-q22 linkage results in eastern Quebec families affected by schizophrenia[J]. Am J Med Genet,2002,114(1):51-55.
[148]MAZIADE M, ROY MA. CHAGNON YC. et al. Shared and specific susceptibility loci for schizophrenia and bipolar disorder:a dense genome scan in Eastern Quebec families[J]. Mol Psychiatry.2005.10(5):486-499.
[149]MCGILLIVRAY BC, BASSETT AS, LANGLOIS S, et al. Familial 5q11.2-q13.3 segmental duplication cosegregating with multiple anomalies, including schizophrenia[J]. Am J Med Genet,1990,35(1):10-13.
[150]MESZAROS K, LENZINGER E, FUREDER T, et al. The influence of phenotype on the outcome of linkage analysis of schizophrenia[J]. Schizophr Res,1996,22(1):89-90.
[151]MOWRY BJ, EWEN KR, NANCARROW DJ, et al. Second stage of a genome scan of schizophrenia:study of five positive regions in an expanded sample[J]. Am J Med Genet,2000,96(6):864-869.
[152]OWEN MJ, WILLIAMS NM, O'DONOVAN MC. The molecular genetics of schizophrenia:new findings promise new insights[J]. Mol Psychiatry,2004, 9(1):14-27.
[153]PARK N, JUO SH, CHENG R, et al. Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia[J]. Mol Psychiatry,2004,9(12):1091-1099.
[154]PAUNIO T, TUULIO-HENRIKSSON A, HIEKKALINNA T, et al. Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q[J]. Hum Mol Genet. 2004,13(16):1693-1702.
[155]PIMM J, MCQUILLIN A, THIRUMALAI S, et al. The Epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia[J]. Am J Hum Genet, 2005,76(5):902-907.
[156]PUJANA MA, MARTORELL L, VOLPINI V, et al. Analysis of amino-acid and nucleotide variants in the spinocerebellar ataxia type 1 (SCA1) gene in schizophrenic patients[J]. Hum Genet,1997,99(6):772-775.
[157]PULVER AE, KARAYIORGOU M, LASSETER VK, et al. Follow-up of a report of a potential linkage for schizophrenia on chromosome 22q12-q13.1: Part 2[J]. Am J Med Genet,1994,54(1):44-50.
[158]PULVER AE. MULLE J. NESTADT G. et al. Genetic heterogeneity in schizophrenia:stratification of genome scan data using co-segregating related phenotypes[J]. Mol Psychiatry,2000,5(6):650-653.
[159]RILEY BP, TAHIR E, RAJAGOPALAN S, et al. A linkage study of the N-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families[J]. Psychiatr Genet,1997,7(2):57-74.
[160]RILEY BP, LIN MW, MOGUDI-CARTER M, et al. Failure to exclude a possible schizophrenia susceptibility locus on chromosome 13q14.1-q32 in southern African Bantu-speaking families[J]. Psychiatr Genet,1998, 8(3):155-162.
[161]ROSA A, FANANAS L, CUESTA MJ, et al.lq21-q22 locus is associated with susceptibility to the reality-distortion syndrome of schizophrenia spectrum disorders[J]. Am J Med Genet,2002.114(5):516-518.
[162]SAVIOUK V, MOREAU MP, TERESHCHENKO IV. et al. Association of synapsin 2 with schizophrenia in families of Northern European ancestry [J]. Schizophr Res,2007,96(1-3):100-111.
[163]SCHWAB SG, LERER B, ALBUS M, et al. Potential linkage for schizophrenia on chromosome 22ql2-ql3:a replication study [J]. Am J Med Genet.1995.60(5):436-443.
[164]SCHWAB SG, HALLMAYER J. LERER B. et al. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis[J]. Am J Hum Genet,1998. 63(4):1139-1152.
[165]SCHWAB SG. HANDOKO HY. KUSUMAWARDHANI A. et al. Genome-wide scan in 124 Indonesian sib-pair families with schizophrenia reveals genome-wide significant linkage to a locus on chromosome 3p26-21[J]. Am J Med Genet B Neuropsychiatr Genet,2008,147B (7):1245-1252.
[166]SEGURADO R, DETERA-WADLEIGH SD. LEVINSON DF, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III:Bipolar disorder[J]. Am J Hum Genet.2003.73(1):49-62.
[167]SHERRINGTON R. BRYNJOLFSSON J. PETURSSON H. et al. Localization of a susceptibility locus for schizophrenia on chromosome 5[J]. Nature,1988, 336(6195):164-167.
[168]SHIHABUDDIN L, SILVERMAN JM, BUCHSBAUM MS, et al. Ventricular enlargement associated with linkage marker for schizophrenia-related disorders in one pedigree[J]. Mol Psychiatry,1996,1(3):215-222.
[169]SHINKAI T, OHMORI O, HORI H, et al. Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia[J]. Mol Psychiatry, 2002,7(6):560-563.
[170]SILVERMAN JM, GREENBERG DA, ALTSTIEL LD, et al. Evidence of a locus for schizophrenia and related disorders on the short arm of chromosome 5 in a large pedigree[J]. Am J Med Genet,1996,67(2):162-171.
[171]SKLAR P, PATO MT, KIRBY A, et al. Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis[J]. Mol Psychiatry,2004,9(2):213-218.
[172]STOBER G, MEYER J, NANDA I, et al. hkCNN3 which maps to chromosome 1q21 is not the causative gene in periodic catatonia. a familial subtype of schizophrenia[J]. Eur Arch Psychiatry Clin Neurosci,2000, 250(4):163-168.
[173]STONE WS, FARAONE SV, SU J, et al. Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample[J]. Am J Med Genet B Neuropsychiatr Genet 2004,127B(1):5-10.
[174]STRAUB RE, MACLEAN CJ, MA Y, et al. Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes[J]. Mol Psychiatry,2002,7(6):542-559.
[175]STRAUB RE, MACLEAN CJ, Martin RB, et al. A schizophrenia locus may be located in region 10p15-p11[J]. Am J Med Genet,1998,81(4):296-301.
[176]SUAREZ BK, DUAN J, SANDERS AR, et al. Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11pl3.1-q14.1 in the combined sample[J]. Am J Hum Genet,2006,78(2):315-333.
[177]TAKAHASHI S, CUI YH, KOJIMA T, et al. Family-based association study of markers on chromosome 22 in schizophrenia using African-American, European-American, and Chinese families [J]. Am J Med Genet B Neuropsychiatr Genet.2003,120B (1):11-17.
[178]TAKAHASHI S, FARAONE SV. LASKY-SU J, et al. Genome-wide scan of homogeneous subtypes of NIMH genetics initiative schizophrenia families[J]. Psychiatry Res,2005,133(2-3):111-122.
[179]TANG RQ, ZHAO XZ, SHI YY, et al. Family-based association study of Epsin 4 and Schizophrenia[J]. Mol Psychiatry,2006,11(4):395-399.
[180]VALLADA HP, GILL M, SHAM P, et al. Linkage studies on chromosome 22 in familial schizophrenia[J]. Am J Med Genet,1995.60(2):139-146.
[181]VAWTER MP, ATZ ME. ROLLINS BL. et al. Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia[J]. Hum Genet,2006,119(5):558-570.
[182]WALSS-BASS C. ESCAMILLA MA. RAVENTOS H, et al. Evidence of genetic overlap of schizophrenia and bipolar disorder:linkage disequilibrium analysis of chromosome 18 in the Costa Rican population[J]. Am J Med Genet B Neuropsychiatr Genet.2005,139B (1):54-60.
[183]WEDENOJA J. LOUKOLA A. TUULIO-HENRIKSSON A. et al. Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia familiesfJ]. Mol Psychiatry,2008, 13(7):673-684.
[184]WEI J, HEMMINGS GP. A further study of a possible locus for schizophrenia on the X chromosome [J]. Biochem Biophys Res Commun,2006,344(4): 1241-1245.
[185]WIJSMAN EM. ROSENTHAL EA. HALL D. et al. Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae:evidence for linkage to chromosome 2q[J]. Mol Psychiatry, 2003.8(7):695-705.
[186]WILLIAMS NM, NORTON N, WILLIAMS H, et al. A systematic genomewide linkage study in 353 sib pairs with schizophrenia[J]. Am J Hum Genet,2003,73(6):1355-1367.
[187]WILLIAMS HJ, NORTON N, PEIRCE T, et al. Association analysis of the glial cell line-derived neurotrophic factor (GDNF) gene in schizophrenia[J]. Schizophr Res,2007,97(1-3):271-276.
[188]YOSHIMI A, TAKAHASHI N, SAITO S, et al. Genetic analysis of the gene coding for DARPP-32 (PPP1R1B) in Japanese patients with schizophrenia or bipolar disorder[J]. Schizophr Res,2008,100(1-3):334-341.
[189]ZHENG Y, WANG X, GU N, et al. A two-stage linkage analysis of Chinese schizophrenia pedigrees in 10 target chromosomes [J]. Biochem Biophys Res Commun,2006,342(4):1049-1057.
[190]GATTAZ WF, KOLLISCH M, THUREN T, et al. Increased plasma phospholipase A2 activity in schizophrenic patients:reduction after neuroleptic therapy[J]. Biol Psychiatry,1987.22(4):421-426.
[191]ADLER NEVO G, MEGED S, SELA BA, et al. Homocysteine levels in adolescent schizophrenia patients[J]. Eur Neuropsychopharmacol,2006,16(8): 588-591.
[192]MUNTJEWERFF JW, KAHN RS, BLOM HJ, et al. Homocysteine, methylenetetrahy drofolate reducase and risk of schizophrenia:a meta-analysis[J]. Mol Psychiatry,2006,11(2):143-149.
[193]BROWN AS, BOTTIGLIERI T, SCHAEFER CA, et al. Elevated prenatal homocysteine levels as a risk factor for schizophrenia [J]. Arch Gen Psychiatry. 2007,64(1):31-39.
[194]SHIMABUKURO M, SASAKI T, IMAMURA A. et al. Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia:A potential link between epigenetics and schizophrenia[J]. J Psychiatr Res.2007.41(12):1042-1046.
[195]SHINKAI T, OHMORI O, HORI H, NAKAMURA J. Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia[J]. Mol Psychiatry,2002,7 (6):560-563.
[196]杨娜,李智.甲基化CpG结合蛋白家族研究进展[J].国际遗传学杂志,2007,30(6)：439-443.
[197]PAYKEL ES, WEISSMAN MM, PRUSOFF BA. Social maladjustment and severity of depression[J]. Compr Psychiatry,1978,19(2):121-128.
[198]陈彦方,李舜伟.脑部疾病诊断治疗学[M].北京：中国协和医科大学出版社，2003：1141.
[199]张明圆.精神科评定量表手册[M].第1版，长沙：湖南科学技术出版社，1993，100-101.
[200]费立鹏,熊卫,赵祖安.精神病阴性阳性症状评定量表使用有关问题[M].第1版,武汉：湖北科学技术出版社,1990,7-43.
[201]LUO J, BERGSTROM DE, BARANY F. Improving the fidelity of thermus thermophilus DNAligase[J]. Nucleic Acids Res,1996,24(15):3071-3078.
[202]JENNEN-STEINMETZ C, LOFFLER W, HAFNER H. Demography and age of onset of schizophrenia[J]. Br J Psychiatry,1997,170:485-486.
[203]DERNOVSEK MZ, TAVCAR R. Age at onset of schizophrenia and neuroleptic dosage[J]. Soc Psychiatry Psychiatr Epidemiol,1999,34(12): 622-626.
[204]RAM R, BROMET EJ, EATON WW, et al. The natural course of schizophrenia:a review of first-admission studies[J]. Schizophr Bull,1992, 18(2):185-207.
[205]HEIDEN A, WILLINGER U, SCHARFETTER J, et al. Anticipation in schizophrenia[J]. Schizophr Res,1999,35(1):25-32.
[206]RITSNER M. S, RATNER Y, GIBEL A, et al. Positive family history is associated with persistent elevated emotional distress in schizophrenia: evidence from a 16-month follow-up study[J]. Psychiatry Res,2007,153(3): 217-223.
[207]MURTHY RS, WIG NN. Dermatoglyphics in schizophrenia:the relevance of positive family hi story [J]. Br J Psychiatry.1977.130:56-58.
[208]FENNIG S. PUTNAM K. BROMET EJ. et al. Gender, premorbid characteristics and negative symptoms in schizophrenia[J].Acta Psychiat Scand, 1995,92(3):173-177.
[209]TORGALSBOEN AK. Full recovery from schizophrenia:the prognostic role of premorbid adjustment, symptoms at first admission, precipitating events and gender[J].Psychiatry Res,1999,88(2):143-152.
[210]DOLLFUS S, EVERITT B. Symptom structure in schizophrenia:two-, three-or four-factor models?[J]. Psychopathology,1998,31(3):120-130.
[211]ROSEN WG, MOHS RC, JOHNS CA, et al. Positive and negative symptoms in schizophrenia[J]. Psychiatry Res,1984,13(4):277-284.
[212]LIU SK, HWU HG, CHEN WJ. Clinical symptom dimensions and deficits on the Continuous Performance Test in schizophrenia[J]. Schizophr Res,1997, 25(3):211-219.
[213]LEBOYER M, JAY M, D'AMATO T, et al. Subtyping familial schizophrenia: reliability, concordance, and stability[J]. Psychiatry Res,1990,34(1):77-88.
[214]KENDLER KS, GRUENBERG AM, TSUANG MT. Subtype stability in schizophrenia[J]. Am J Psychiatry,1985,142(7):827-332.
[215]FENTON WS, MCGLASHAN TH. Natural history of schizophrenia subtypes. I. Longitudinal study of paranoid, hebephrenic, and undifferentiated schizophrenia[J]. Arch Gen Psychiatry.1991,48(11):969-977.
[216]郭本仁,张文林，查智群,等.155例精神分裂症患者EPQ测试结果分析[J].江苏医药，1997,23(5)：328-329.
[217]BERENBAUM H, FUJITA F. Schizophrenia and personality:exploring the boundaries and connections between vulnerability and outcome[J]. J Abnorm Psychol,1994,130(1):148-158.
[218]HERRAN A, SIERRA-BIDDLE D, CUESTA MJ, et al. Can personality traits help us explain disability in chronic schizophrenia?[J]. Psychiatry Clin Neurosci,2006,60(5):538-545.
[219]HENDRICH B. BIRD A. Identification and characterization of a family of mammalian methyl-CpG binding proteins[J]. Mol Cell Biol.1998,18(11): 6538-6547.
[220]ZHAO X, UEBA T, CHRISTIE, BR, et al. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function[J]. Proc Natl Acad Sci USA,2003,100(11):6777-6782.
[221]HENDRICH B, GUY J, RAMSAHOYE B, et al. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse developmen[J]. Genes Dev,2001,15(6):710-723.
[222]SALOZHIN SV, PROKHORCHUK EB, GEORGIEV GP. Methylation of DNA--one of the major epigenetic markers[J]. Biochemistry (Mosc),2005, 70(5):525-532.
[223]ZHANG Y, NG HH, ERDJUMENT-BROMAGE H. et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation[J]. Genes Dev,1999,13(15):1924-1935.