儿茶酚氧位甲基转移酶基因多态性与精神分裂症的关系研究
摘要
精神分裂症(以下简称精分症)是人类最常见的精神性疾患之一。在我国,精分症的终身患病率高达0.7%左右。精分症不仅给家庭和社会带来沉重的经济负担,而且还严重威胁社会的安全与稳定。确定精分症的病因从而防治精分症是医学界乃至整个社会迫切需要解决的问题。遗传流行病学研究证实,精分症与遗传因素有密切关系,但不符合经典的孟德尔单基因遗传规律,属于多基因遗传病或人类复杂疾病。人类基因组系统扫描发现,除19 号,21 号和Y 染色体以外,其余的染色体上都可能含有精分症易感基因。但是,能获得较好重复性的染色体区域至少有6个,包括1q21-22、5q22-23、6p24-21、8p22-21、13q14-33和22q11-12。
本研究工作以中国汉族精分症患者和他们的健康父母双亲组成的核心家系为研究对象,研究22q11.2 染色体区域上的儿茶酚氧位甲基转移酶(COMT)基因上的3 个SNPs 位点,用聚合酶链式反应–限制性片段长度多态性(PCR–RFLP)方法检测个体基因型,用SPSS 统计学软件及EXCEL软件管理基因分型数据,应用基于家系的连锁不平衡分析方法(TDT 及HRR)和多功能遗传统计学软件(SPSS、UNPHASED 和Transmit)分析数据,确定COMT 基因与精分症的关系。结果显示,各位点与精神分裂症无关联,但发现与精神分裂症的某些阳性症状即不同临床表型高度相关,提示COMT 基因与精神分裂症的临床表型的发生密切相关。
Schizophrenia is a common mental disorder with a life-time prevalence of 1% in the general population worldwide, the life-time prevalence is 0.7% in China. The large suffering population has brought heavy economic burden to the society and families, threatening the safety and stability of society. Therefore, it urgently important for the medical field and the whole society to determine the ecological factors of schizophrenia so as to preventive and cure it. Epidemiological study has indicated that the mechanism of schizophrenia is mainly related to genetic components. Although genetic component may play a role in schizophrenia, it is not a simple Mendelian disease but it looks like a complex disease with a polygenic mechanism. Genome-wide scanning shows that all the chromosomes except for chromosome 19, 21 and Y, may contain a schizophrenia susceptibility gene, while there are only 6 chromosome regions whose positive regions could have a better reproducibility. They are1q21-22、5q22-23、6p24-21、8p22-21、13q14-33 and 22q11-12.
This study was designed to search for a susceptibility gene for schizophrenia by screening three SNPs on catechol-o-methyltransferase (COMT)gene, a candidate gene of schizophrenia in 22q11.2 gene. This study used a family-based LD analysis in which the family trios, consisting of father, mother and affected offspring were recruited. They were all Chinese Han decent in North China. Polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP)were adopted to examine individual genotype. Statistical software SPSS and EXCEL were used to handle the data on genotype. Goodness of fit χ2 test was used to detect whether SNPs distribution in the sample population is in Hardy-Weinberg equilibrium Multifunctional genetic statistical software were used to detect whether the tested SNPs locus was associated with schizophrenia by two family-based LD analysis, the haplotype relative risk
本研究工作以中国汉族精分症患者和他们的健康父母双亲组成的核心家系为研究对象,研究22q11.2 染色体区域上的儿茶酚氧位甲基转移酶(COMT)基因上的3 个SNPs 位点,用聚合酶链式反应–限制性片段长度多态性(PCR–RFLP)方法检测个体基因型,用SPSS 统计学软件及EXCEL软件管理基因分型数据,应用基于家系的连锁不平衡分析方法(TDT 及HRR)和多功能遗传统计学软件(SPSS、UNPHASED 和Transmit)分析数据,确定COMT 基因与精分症的关系。结果显示,各位点与精神分裂症无关联,但发现与精神分裂症的某些阳性症状即不同临床表型高度相关,提示COMT 基因与精神分裂症的临床表型的发生密切相关。
Schizophrenia is a common mental disorder with a life-time prevalence of 1% in the general population worldwide, the life-time prevalence is 0.7% in China. The large suffering population has brought heavy economic burden to the society and families, threatening the safety and stability of society. Therefore, it urgently important for the medical field and the whole society to determine the ecological factors of schizophrenia so as to preventive and cure it. Epidemiological study has indicated that the mechanism of schizophrenia is mainly related to genetic components. Although genetic component may play a role in schizophrenia, it is not a simple Mendelian disease but it looks like a complex disease with a polygenic mechanism. Genome-wide scanning shows that all the chromosomes except for chromosome 19, 21 and Y, may contain a schizophrenia susceptibility gene, while there are only 6 chromosome regions whose positive regions could have a better reproducibility. They are1q21-22、5q22-23、6p24-21、8p22-21、13q14-33 and 22q11-12.
This study was designed to search for a susceptibility gene for schizophrenia by screening three SNPs on catechol-o-methyltransferase (COMT)gene, a candidate gene of schizophrenia in 22q11.2 gene. This study used a family-based LD analysis in which the family trios, consisting of father, mother and affected offspring were recruited. They were all Chinese Han decent in North China. Polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP)were adopted to examine individual genotype. Statistical software SPSS and EXCEL were used to handle the data on genotype. Goodness of fit χ2 test was used to detect whether SNPs distribution in the sample population is in Hardy-Weinberg equilibrium Multifunctional genetic statistical software were used to detect whether the tested SNPs locus was associated with schizophrenia by two family-based LD analysis, the haplotype relative risk
引文
1 沈渔邨, 精神病学, 北京:北京人民卫生出版社, 1994, 574.
2 Gottesman I. Schizophrenia: the Epigenetic puzzle, Cambridge press, New York, 1982.
3 Mowary B, Nancarrow D. Proceedings of the Australian neuroscience society symposium: schizophrenia molecular genetics of schizophrenia. Clinical and experimental pharmacology and physiology.2001, 28:66.
4 金卫东, 刘小林. 精神分裂症. 北京:中国医药科技出版社. 1998, 33.
5 Harrison PJ, Owen MJ. Gene for schizophrenia? Resent findings and their pathophysiological Implications. Lancet. 2003, 361:417～419.
6 陈刚,贺林. 精神分裂症的遗传学及基因定位.中华精神科杂志,2004,37(1):49～51.
7 Pulver AE, Liang KY, Brown H, et al. Risk factors in schizophrenia: season of birth, gender and familial risk. Br J Psychiatry, 1992, 160: 65～71.
8 Torrey EF, Mille J, Rawlings R, et al. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res, 1997, 28: 1～38.
9 罗开林. 精神分裂症分析流行病学的假说相关性研究. 中华神经精神科杂志, 1993, 19: 7.
10 Lin YQ. Correlative study on analytical epidemiology between the morbidity of schizophrenia and the psychsocial factors. Health Psychology Journal, 2002, 10: 124～126.
11 Brown GW, Harris T and Peto J. Life events and psychiatic disorders, Part II, Nature of the causal Link. Psychological Medicine, 1973, 3: 159.
12 Harder D. Life events and psychopathology sererity among first psychiatric admissions. Tournal of abnormal psychology, 1980, 89: 165.
13 汤毓华. 生活事件与精神分裂症. 国外医学·精神病学分册,1987, 14: 6～9.
14 张亚林. 生活事件的致病作用. 中国神经精神疾病杂志, 1988, 14: 65～68.
15 陈昌惠, 沈渔邨, 张维熙等. 中国七地区精神分裂症流行病学调查. 中神经精神科杂志, 1998, 31: 72.
16 Susser E, Neugebarer R, Hoek H, et al. Schizophrenia after prenatal famine: further evidence. Arch Gen psychiatry, 1996, 53: 25～31.
17 吴怀安, 曾瑞萍, 杜传书. 精神分裂症遗传标记的研究. 国外医学·遗传学分册, 1994, 5: 247～249.
18 Joseph MH, Frith CD, Waddington JL. Dopaminergic mechanisms and cognitive deficit in schizophrenia. A neurobiological model. Psychopharmacology (Berl), 197, 63: 273～280.
19 范建华, 沈渔邨, 周朝凤等. 汉族酒依赖高发家系单胺氧化酶A 基因多态性的对照研究. 中华精神科杂志, 1999, 32: 160～163.
20 Wyatt RJ, Murphy DL, Belmaker R, et al. Reduced monoamine oxidase activity in platelets: a possible genetic marker for vulnerability to schizophrenia. Science, 1973, 179: 916～918.
21 Carlsson M, Carlsson A. Schizophrenia: a subcortical neurotransmitter imbalance syndrome? Schizophr Bull, 1990, 16: 425～432.
22 许琪. 精神分裂症遗传易感性研究进展. 基础医学与临床,2004,24(5):497～503.
23 Gershon ES, Badner JA, Goldin LR, Sanders AR, Cravchik A, Detera-Wadleigh SD. Closing in on genes for manic-depressive illness and schizophrenia. Neuro psycho pharmacology. 1998;18:233～242.
24 Thomson G. Mapping disease genes:family-based association studies. Am J Hum Genet.1995,57:487～498.
25 Bellodi L, Bussoleni C, Scorza-Smeraldi R, Grassi G, Zaechetti L, Smeraldi E. Family study of schizophrenia: exploratory analysis for relevant factors. Schizopr Bull.1986,12:120～128.
26 Richard S, Spielman, Warren J, Ewwns. The TDT and other family-based for linkage disequilibrium and association. Am J Genet.1996,59:983～989.
27 吴怀安.儿茶酚氧位甲基转移酶与精神障碍相关性研究.现代康复,2001,5(3):107～108.
28 Kaakkola S,Ctordin A,Mannisito PT. General properties and clinical possibilities of new selective inhibitors of catechol-O-methyltransferase. Gen Pharmac,1994,25:813～824
29 贺斌.COMT 抑制剂治疗帕金森病展望.国外医药·合成药生化药制剂分册,2001,22(1):29～31.
30 Dunham I, Shimizu N, Roe BA, et al. The DNA sequence of human chromosome 22.Nature, 1999, 402(67617): 489～495.
31 De’Chaldee M, Laurent C, Thibaut F, et al. Linkage disequilibrium on the COMT gene in French schizophrenics and controls. Am J Med Genet, 1999, 88(5): 452～457.
32 Karaiogou M, Morris MA, Morrow B, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proceedings of the National Academy of Sciences USA, 1995, 92: 7612～7616.
33 Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001,98:6917～6922.
34 Kunugi H, Vallada HP, Sham PC, Hoda F, Arranz MJ, Li T, Nanko S, Murray RM, McGuffin P, Owen M, Gill M, Collier DA. Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet.1997, 7:97～101.
35 Wonodi IW, Stine OC, Mitchell BD, Buchanan RW, Thaker GK. Association between Val108/158met polymorphism of the COMT gene and schizophrenia. Am J Med Genet. 2003, 120: 47～50.
36 Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry. 2005, 15,57(2):139～44.
37 费立鹏,熊卫,赵祖安等. 精神病阴性、阳性症状评定量表使用有关问题. 湖北科学技术出版社, 1990, 第一版:7～43.
38 张明园. 精神科评定量表手册. 湖南科学技术出版社, 1993, 第一版:100～101.
39 Berry N,Jobanputra V. Molecular genetics of schizophrenia::a critical review. Psychiatry Neurosce.2003,28:415～424.
40 Ohmori O, Shinkai T, Kojima H, et al. Association study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenia. Neurosci Lett, 1998, 243(1-3): 109～112.
41 Strous RD, Bark N, Parsia SS, et al. Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res, 1997, 69(2-3): 71～77.
42 Daniels JK, Williams NM, Williams J, et al. No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity.
2 Gottesman I. Schizophrenia: the Epigenetic puzzle, Cambridge press, New York, 1982.
3 Mowary B, Nancarrow D. Proceedings of the Australian neuroscience society symposium: schizophrenia molecular genetics of schizophrenia. Clinical and experimental pharmacology and physiology.2001, 28:66.
4 金卫东, 刘小林. 精神分裂症. 北京:中国医药科技出版社. 1998, 33.
5 Harrison PJ, Owen MJ. Gene for schizophrenia? Resent findings and their pathophysiological Implications. Lancet. 2003, 361:417～419.
6 陈刚,贺林. 精神分裂症的遗传学及基因定位.中华精神科杂志,2004,37(1):49～51.
7 Pulver AE, Liang KY, Brown H, et al. Risk factors in schizophrenia: season of birth, gender and familial risk. Br J Psychiatry, 1992, 160: 65～71.
8 Torrey EF, Mille J, Rawlings R, et al. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res, 1997, 28: 1～38.
9 罗开林. 精神分裂症分析流行病学的假说相关性研究. 中华神经精神科杂志, 1993, 19: 7.
10 Lin YQ. Correlative study on analytical epidemiology between the morbidity of schizophrenia and the psychsocial factors. Health Psychology Journal, 2002, 10: 124～126.
11 Brown GW, Harris T and Peto J. Life events and psychiatic disorders, Part II, Nature of the causal Link. Psychological Medicine, 1973, 3: 159.
12 Harder D. Life events and psychopathology sererity among first psychiatric admissions. Tournal of abnormal psychology, 1980, 89: 165.
13 汤毓华. 生活事件与精神分裂症. 国外医学·精神病学分册,1987, 14: 6～9.
14 张亚林. 生活事件的致病作用. 中国神经精神疾病杂志, 1988, 14: 65～68.
15 陈昌惠, 沈渔邨, 张维熙等. 中国七地区精神分裂症流行病学调查. 中神经精神科杂志, 1998, 31: 72.
16 Susser E, Neugebarer R, Hoek H, et al. Schizophrenia after prenatal famine: further evidence. Arch Gen psychiatry, 1996, 53: 25～31.
17 吴怀安, 曾瑞萍, 杜传书. 精神分裂症遗传标记的研究. 国外医学·遗传学分册, 1994, 5: 247～249.
18 Joseph MH, Frith CD, Waddington JL. Dopaminergic mechanisms and cognitive deficit in schizophrenia. A neurobiological model. Psychopharmacology (Berl), 197, 63: 273～280.
19 范建华, 沈渔邨, 周朝凤等. 汉族酒依赖高发家系单胺氧化酶A 基因多态性的对照研究. 中华精神科杂志, 1999, 32: 160～163.
20 Wyatt RJ, Murphy DL, Belmaker R, et al. Reduced monoamine oxidase activity in platelets: a possible genetic marker for vulnerability to schizophrenia. Science, 1973, 179: 916～918.
21 Carlsson M, Carlsson A. Schizophrenia: a subcortical neurotransmitter imbalance syndrome? Schizophr Bull, 1990, 16: 425～432.
22 许琪. 精神分裂症遗传易感性研究进展. 基础医学与临床,2004,24(5):497～503.
23 Gershon ES, Badner JA, Goldin LR, Sanders AR, Cravchik A, Detera-Wadleigh SD. Closing in on genes for manic-depressive illness and schizophrenia. Neuro psycho pharmacology. 1998;18:233～242.
24 Thomson G. Mapping disease genes:family-based association studies. Am J Hum Genet.1995,57:487～498.
25 Bellodi L, Bussoleni C, Scorza-Smeraldi R, Grassi G, Zaechetti L, Smeraldi E. Family study of schizophrenia: exploratory analysis for relevant factors. Schizopr Bull.1986,12:120～128.
26 Richard S, Spielman, Warren J, Ewwns. The TDT and other family-based for linkage disequilibrium and association. Am J Genet.1996,59:983～989.
27 吴怀安.儿茶酚氧位甲基转移酶与精神障碍相关性研究.现代康复,2001,5(3):107～108.
28 Kaakkola S,Ctordin A,Mannisito PT. General properties and clinical possibilities of new selective inhibitors of catechol-O-methyltransferase. Gen Pharmac,1994,25:813～824
29 贺斌.COMT 抑制剂治疗帕金森病展望.国外医药·合成药生化药制剂分册,2001,22(1):29～31.
30 Dunham I, Shimizu N, Roe BA, et al. The DNA sequence of human chromosome 22.Nature, 1999, 402(67617): 489～495.
31 De’Chaldee M, Laurent C, Thibaut F, et al. Linkage disequilibrium on the COMT gene in French schizophrenics and controls. Am J Med Genet, 1999, 88(5): 452～457.
32 Karaiogou M, Morris MA, Morrow B, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proceedings of the National Academy of Sciences USA, 1995, 92: 7612～7616.
33 Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001,98:6917～6922.
34 Kunugi H, Vallada HP, Sham PC, Hoda F, Arranz MJ, Li T, Nanko S, Murray RM, McGuffin P, Owen M, Gill M, Collier DA. Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet.1997, 7:97～101.
35 Wonodi IW, Stine OC, Mitchell BD, Buchanan RW, Thaker GK. Association between Val108/158met polymorphism of the COMT gene and schizophrenia. Am J Med Genet. 2003, 120: 47～50.
36 Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry. 2005, 15,57(2):139～44.
37 费立鹏,熊卫,赵祖安等. 精神病阴性、阳性症状评定量表使用有关问题. 湖北科学技术出版社, 1990, 第一版:7～43.
38 张明园. 精神科评定量表手册. 湖南科学技术出版社, 1993, 第一版:100～101.
39 Berry N,Jobanputra V. Molecular genetics of schizophrenia::a critical review. Psychiatry Neurosce.2003,28:415～424.
40 Ohmori O, Shinkai T, Kojima H, et al. Association study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenia. Neurosci Lett, 1998, 243(1-3): 109～112.
41 Strous RD, Bark N, Parsia SS, et al. Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res, 1997, 69(2-3): 71～77.
42 Daniels JK, Williams NM, Williams J, et al. No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity.