DTNBP1和NRG1基因是中国汉族人群精神分裂症的易感基因
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摘要
精神分裂症是一种严重的精神疾病，发病率大约为1%，多数病人终身不愈。遗传因素对该疾病有很重要的影响，多年来为了寻找提高精神分裂症风险的DNA序列上的突变已付出了巨大的努力，然而该病的遗传方式非常复杂，并不符合简单的孟德尔遗传规律。精神分裂症的病因机制可能涉及多个相互作用的微效基因，未知的环境因素可能也有一定的影响，再加上该疾病诊断上的不明确，这些都使得遗传分析至今还没有获得令人满意的结果。目前鉴定精神分裂症易感基因最主要的方法是连锁分析、连锁不平衡分析、和染色体异常研究。在过去的20年中，报道过许多连锁研究，但一直没有得到能被普遍重复的明确无疑的连锁结果，而连锁不平衡研究的结果也常常是似是而非。
然而最近两年，随着人类全基因组测序的完成，单核苷酸多态标记鉴定和基因分型技术的飞速发展，以及全基因组扫描研究国际合作的开展，多个精神分裂症的染色体可能区域被许多独立的遗传研究所证实。一些研究小组进一步在这些染色体区域开展了系统的精细定位，他们找到了多个可能与精神分裂症有关的基因，而且提供的证据无论是从遗传统计上还是神经生物学上都是可靠和令人信服的。但是，在这些研究发现被完全肯定之前，确凿无疑的重复研究仍然是最重要的。本论文工作对其中两个高度可能的易感基因提供了独立的统计证据，这两个基因分别是6号染色体22.3区域的DTNBP1 (dystrobrevin-binding protein 1)基因和8号染色体12区域的NRG1(Neuregulin 1)基因。
我们对DTNBP1基因中的5个SNPs在233个中国汉族三口之家样品中进行了连锁不平衡分析。SNPs的基因分型采用了结合实时定量PCR的等位基因特异性PCR扩增方法。尽管单个遗传标记分析没有发现一个SNP达到设定的显著性水平（P＝0.05），用TRANSMIT （v 2.5）软件进行的传递不平衡检验却发现这些SNPs
组成的单倍型表现出与精神分裂症显著相关（global P = 0.0007- 0.0009）。对于NRG1基因，我们在中国汉族人群中采用的是病例－对照研究方法，包括540个精神分裂症患者和279个对照样品，分析了NRG1基因5'端外显子边界区域的13个微卫星遗传标记。基因分型实验是在MegaBACE 1000仪器上进行的，采用了荧光微卫星毛细管电泳的方法。单个位点关联分析发现多个微卫星标记在病人组和对照组的频率分布有显著性的差异。根据这13个微卫星两两之间的连锁不平衡程度将它们分成4个区域，单倍型分析发现两个相邻的区域表现出与精神分裂症的关联，CLUMP软件统计结果分别为：T2 X2=57.8, 19df, P=0.00003和T2 X2=49.23, 19df, P=0.000267。结合其它研究小组在欧洲人群中进行的遗传分析结果，我们认为DTNBP1 和 NRG1基因可能影响了中国汉族人群对精神分裂症的易感性。
Schizophrenia is a mental disorder that affects approximately 1% of the population with lifelong devastating consequences. Based on evidence for a major contribution of genetic factors, decades of extensive efforts have been dedicated to the search of DNA sequence variations that increase the risk to SCZ. However, the mode of transmission is complex and non-Mendelian. Several factors such as possible involvement of numerous interactive genes of minor effect, yet unknown environmental effects and diagnostic ambiguities of the disease have made genetic studies in SCZ quite unproductive. The main approaches used to identify susceptibility genes are linkage and linkage disequilibrium studies and the study of cytogenetic abnormalities associated with or linked to schizophrenia. For the past 20 years, many linkage studies have been reported but have failed as yet to produce unequivocal, replicated demonstrations of linkage, while for sporadic cases, linkage disequilibirium studies have been performed but the outcome of such studies has also been quite modest.
However, in the last two years, because of the availability of the
complete human genomic sequence, along with technology advances and cost reductions in SNP identification and genotyping and the coordination of genome-wide scans by world wide consortia, many promising chromosome regions now have support from multiple independent studies. With fine mapping in these regions, several research groups recently announced discovering of susceptibility genes of schizophrenia. The evidence for these genes being involved in the etiology of schizophrenia were statistically robust and also neurobiologically plausible. But before firm acceptance, unequivocal replications remain the top priority. In the present study, we supplied independent statistical support of two of these most promising susceptibility genes: 6p22.3 gene DTNBP1 (dystrobrevin-binding protein 1) and 8p12 gene NRG1 (Neuregulin 1), which might play a role in the etiology of schizophrenia in Chinese Han population.
We performed family-based allelic association study of 5 SNPs within DTNBP1 gene in 233 Han Chinese trios. The genotyping assay used in this study combined kinetic (real-time quantitative) PCR with allele-specific amplification, in which primers were designed to specifically amplify the reference allele or its variant in separate PCR reactions. Although no individual SNP was significant at the P=0.05 level, transmission/disequilibrium test of their haplotypes with TRANSMIT v 2.5 revealed a significant association with the disease (global P=0.0007- 0.0009). As for NRG1, we report a result obtained from a case-control study in the Chinese population (540 schizophrenics, 279 controls). 13 microsatellites within the boundaries of the 5' exon of the NRG1 gene were
genotyped by fluorescence microsatellite electrophoresis on MegaBACE 1000 instruments. Based on the LD pattern of this region, the result from the haplotype analysis indicated that two adjoining regions were associated with schizophrenia (T2 X2=57.8, 19df, P=0.00003; T2 X2=49.23, 19df, P=0.000267, using CLUMP). Along with the data obtained from the previous genetic studies in European samples, our findings suggest that the DTNBP1 and NRG1 gene might influence susceptibility to schizophrenia in Han Chinese population.
然而最近两年，随着人类全基因组测序的完成，单核苷酸多态标记鉴定和基因分型技术的飞速发展，以及全基因组扫描研究国际合作的开展，多个精神分裂症的染色体可能区域被许多独立的遗传研究所证实。一些研究小组进一步在这些染色体区域开展了系统的精细定位，他们找到了多个可能与精神分裂症有关的基因，而且提供的证据无论是从遗传统计上还是神经生物学上都是可靠和令人信服的。但是，在这些研究发现被完全肯定之前，确凿无疑的重复研究仍然是最重要的。本论文工作对其中两个高度可能的易感基因提供了独立的统计证据，这两个基因分别是6号染色体22.3区域的DTNBP1 (dystrobrevin-binding protein 1)基因和8号染色体12区域的NRG1(Neuregulin 1)基因。
我们对DTNBP1基因中的5个SNPs在233个中国汉族三口之家样品中进行了连锁不平衡分析。SNPs的基因分型采用了结合实时定量PCR的等位基因特异性PCR扩增方法。尽管单个遗传标记分析没有发现一个SNP达到设定的显著性水平（P＝0.05），用TRANSMIT （v 2.5）软件进行的传递不平衡检验却发现这些SNPs
组成的单倍型表现出与精神分裂症显著相关（global P = 0.0007- 0.0009）。对于NRG1基因，我们在中国汉族人群中采用的是病例－对照研究方法，包括540个精神分裂症患者和279个对照样品，分析了NRG1基因5'端外显子边界区域的13个微卫星遗传标记。基因分型实验是在MegaBACE 1000仪器上进行的，采用了荧光微卫星毛细管电泳的方法。单个位点关联分析发现多个微卫星标记在病人组和对照组的频率分布有显著性的差异。根据这13个微卫星两两之间的连锁不平衡程度将它们分成4个区域，单倍型分析发现两个相邻的区域表现出与精神分裂症的关联，CLUMP软件统计结果分别为：T2 X2=57.8, 19df, P=0.00003和T2 X2=49.23, 19df, P=0.000267。结合其它研究小组在欧洲人群中进行的遗传分析结果，我们认为DTNBP1 和 NRG1基因可能影响了中国汉族人群对精神分裂症的易感性。
Schizophrenia is a mental disorder that affects approximately 1% of the population with lifelong devastating consequences. Based on evidence for a major contribution of genetic factors, decades of extensive efforts have been dedicated to the search of DNA sequence variations that increase the risk to SCZ. However, the mode of transmission is complex and non-Mendelian. Several factors such as possible involvement of numerous interactive genes of minor effect, yet unknown environmental effects and diagnostic ambiguities of the disease have made genetic studies in SCZ quite unproductive. The main approaches used to identify susceptibility genes are linkage and linkage disequilibrium studies and the study of cytogenetic abnormalities associated with or linked to schizophrenia. For the past 20 years, many linkage studies have been reported but have failed as yet to produce unequivocal, replicated demonstrations of linkage, while for sporadic cases, linkage disequilibirium studies have been performed but the outcome of such studies has also been quite modest.
However, in the last two years, because of the availability of the
complete human genomic sequence, along with technology advances and cost reductions in SNP identification and genotyping and the coordination of genome-wide scans by world wide consortia, many promising chromosome regions now have support from multiple independent studies. With fine mapping in these regions, several research groups recently announced discovering of susceptibility genes of schizophrenia. The evidence for these genes being involved in the etiology of schizophrenia were statistically robust and also neurobiologically plausible. But before firm acceptance, unequivocal replications remain the top priority. In the present study, we supplied independent statistical support of two of these most promising susceptibility genes: 6p22.3 gene DTNBP1 (dystrobrevin-binding protein 1) and 8p12 gene NRG1 (Neuregulin 1), which might play a role in the etiology of schizophrenia in Chinese Han population.
We performed family-based allelic association study of 5 SNPs within DTNBP1 gene in 233 Han Chinese trios. The genotyping assay used in this study combined kinetic (real-time quantitative) PCR with allele-specific amplification, in which primers were designed to specifically amplify the reference allele or its variant in separate PCR reactions. Although no individual SNP was significant at the P=0.05 level, transmission/disequilibrium test of their haplotypes with TRANSMIT v 2.5 revealed a significant association with the disease (global P=0.0007- 0.0009). As for NRG1, we report a result obtained from a case-control study in the Chinese population (540 schizophrenics, 279 controls). 13 microsatellites within the boundaries of the 5' exon of the NRG1 gene were
genotyped by fluorescence microsatellite electrophoresis on MegaBACE 1000 instruments. Based on the LD pattern of this region, the result from the haplotype analysis indicated that two adjoining regions were associated with schizophrenia (T2 X2=57.8, 19df, P=0.00003; T2 X2=49.23, 19df, P=0.000267, using CLUMP). Along with the data obtained from the previous genetic studies in European samples, our findings suggest that the DTNBP1 and NRG1 gene might influence susceptibility to schizophrenia in Han Chinese population.
引文
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第三部分 硕博期间已发表和已成文的论文目录
1. JX Tang, JB Fan, NF Gu, GY Feng, ZX Chen, ZS Gao, Y Cheng, XD Sun, G Chen, G Breen, D St Clair, L He. Does MAOA contribute to the clinical characteristics of schizophrenia? In preparation
2. JX Tang, WY Chen, G He, NF Gu, GY Feng, L He. Further evidence to confirm that Neuregulin 1 is associated with schizophrenia in the Chinese population. Molecular Psychiatry (Revised)
3. JX Tang, J Zhou, JB Fan, XW Li, YY Shi, NF Gu, GY Feng, YL Xing, JG Shi, L He. Family-based association study of DTNBP1 in 6p22.3 and schizophrenia. Molecular Psychiatry (In press)
4. JB Fan, Ma J, Zhang CS, Tang JX, Gu NF, Feng GY, St Clair D, He L (2003) A family-based association study of T1945C polymorphism in the proline dehydrogenase gene and schizophrenia in the Chinese population. Neurosci Lett 338:252-4
5. JB Fan, WY Chen, JX Tang, S Li, NF Gu, GY Feng, G Breen, D St Clair, L He (2002) Family-based association studies of COMT gene polymorphisms and schizophrenia in Chinese population. Molecular Psychiatry, 7: 446-452
6. JB Fan*, JX Tang*, NF Gu,GY Feng, FG Zou, YL Xing, JG Shi, SM Zhao, SM Zhu, LP Ji, WW Sun, YL Zheng, WQ Liu, G Breen, D St Clair, L He (2002) A family-based and case-control association study of the NOTCH4 gene and schizophrenia. Molecular Psychiatry, 7: 100-103 (* contributed equally to this work)
7. 面对精神疾病时代的挑战 贺林, 樊金波, 唐君霞《2002 年科学发展报告》科学出版社，北京，95-99。
8. JX Tang, G Breen, L He, D St Clair (2002) Medium scale SNP genotyping studies in complex disease: optimal strategies and application to psychiatric disorders. Poster presentation at HGM 2002- HUGO's 7th International Conference on the Human Genome, April 14-17, Shanghai, China
9. JX Tang (2002) Towards a gel free laboratory: a review of application of DNA melting curve analysis. Slide presentation at HGM 2002- HUGO's 7th International Conference on the Human Genome (for Thermo Hybaid), April 14-17, Shanghai, China
JX Tang, JB Fan, NF Gu, GY Feng, ZX Chen, ZS Gao, Y Cheng, XD
10. Sun, G Chen, G Breen, D St Clair, L He (2000) Association studies of MAOA-proVNTR polymorphism and schizophrenia using a cohort of case-control-based and trios family-based Han Chinese samples. Poster presentation at The 3rd HUGO pacific meeting and the 4th Asia-Pacific conference on Human genetics, October 18-21, Shanghai, China
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第三部分 硕博期间已发表和已成文的论文目录
1. JX Tang, JB Fan, NF Gu, GY Feng, ZX Chen, ZS Gao, Y Cheng, XD Sun, G Chen, G Breen, D St Clair, L He. Does MAOA contribute to the clinical characteristics of schizophrenia? In preparation
2. JX Tang, WY Chen, G He, NF Gu, GY Feng, L He. Further evidence to confirm that Neuregulin 1 is associated with schizophrenia in the Chinese population. Molecular Psychiatry (Revised)
3. JX Tang, J Zhou, JB Fan, XW Li, YY Shi, NF Gu, GY Feng, YL Xing, JG Shi, L He. Family-based association study of DTNBP1 in 6p22.3 and schizophrenia. Molecular Psychiatry (In press)
4. JB Fan, Ma J, Zhang CS, Tang JX, Gu NF, Feng GY, St Clair D, He L (2003) A family-based association study of T1945C polymorphism in the proline dehydrogenase gene and schizophrenia in the Chinese population. Neurosci Lett 338:252-4
5. JB Fan, WY Chen, JX Tang, S Li, NF Gu, GY Feng, G Breen, D St Clair, L He (2002) Family-based association studies of COMT gene polymorphisms and schizophrenia in Chinese population. Molecular Psychiatry, 7: 446-452
6. JB Fan*, JX Tang*, NF Gu,GY Feng, FG Zou, YL Xing, JG Shi, SM Zhao, SM Zhu, LP Ji, WW Sun, YL Zheng, WQ Liu, G Breen, D St Clair, L He (2002) A family-based and case-control association study of the NOTCH4 gene and schizophrenia. Molecular Psychiatry, 7: 100-103 (* contributed equally to this work)
7. 面对精神疾病时代的挑战 贺林, 樊金波, 唐君霞《2002 年科学发展报告》科学出版社，北京，95-99。
8. JX Tang, G Breen, L He, D St Clair (2002) Medium scale SNP genotyping studies in complex disease: optimal strategies and application to psychiatric disorders. Poster presentation at HGM 2002- HUGO's 7th International Conference on the Human Genome, April 14-17, Shanghai, China
9. JX Tang (2002) Towards a gel free laboratory: a review of application of DNA melting curve analysis. Slide presentation at HGM 2002- HUGO's 7th International Conference on the Human Genome (for Thermo Hybaid), April 14-17, Shanghai, China
JX Tang, JB Fan, NF Gu, GY Feng, ZX Chen, ZS Gao, Y Cheng, XD
10. Sun, G Chen, G Breen, D St Clair, L He (2000) Association studies of MAOA-proVNTR polymorphism and schizophrenia using a cohort of case-control-based and trios family-based Han Chinese samples. Poster presentation at The 3rd HUGO pacific meeting and the 4th Asia-Pacific conference on Human genetics, October 18-21, Shanghai, China