基于核心家系的EGR3基因与精神分裂症的关联研究

doi:10.3724/SP.J.1005.2012.00307

遗传 ›› 2012, Vol. 34 ›› Issue (3): 307-314.doi: 10.3724/SP.J.1005.2012.00307

基于核心家系的EGR3基因与精神分裂症的关联研究

宁启兰¹, 马旭东¹, 焦李子¹, 牛晓蓉¹, 李建鹏¹, 王彬¹, 张欢², 马捷¹

1. 西安交通大学医学院遗传学与分子生物学系, 西安 710061 2. 西安交通大学第二附属医院精神科, 西安 710004

收稿日期:2011-06-10 修回日期:2011-09-26 出版日期:2012-03-20 发布日期:2012-03-25
通讯作者: 马捷 E-mail:majie@mail.xjtu.edu.cn
基金资助:
国家自然科学基金项目(编号: 30800618)和国家大学生创新性实验项目(编号: 101069863)资助

A family-based association study of the EGR3 gene polymorphisms and schizophrenia

NING Qi-Lan¹, MA Xu-Dong¹, JIAO Li-Zi¹, NIU Xiao-Rong¹, LI Jian-Peng¹, WANG Bin¹, ZHANG Huan², MA Jie¹

1. Department of Genetics and Molecular Biology, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China 2. Department of Psychiatry, the Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 710004, China

Received:2011-06-10 Revised:2011-09-26 Online:2012-03-20 Published:2012-03-25
Contact: MA Jie E-mail:majie@mail.xjtu.edu.cn

摘要/Abstract

摘要： 研究表明位于染色体8p21.3区域的EGR3(Early growth response 3)是精神分裂症(Schizophrenia)的重要易感基因, 然而, 仍有两个病例-对照研究未能验证上述发现。为了研究EGR3基因在我国患者中是否与疾病关联, 文章在中国汉族的核心家系中选择EGR3基因座位上的5个SNPs位点(rs1996147、rs1877670、rs3750192、rs35201266和rs7009708)进行基因分型和传递不平衡检验(Transmission disequilibrium test, TDT)。结果表明遗传标记rs1996147和rs3750192分别显示出显著的传递不平衡(c²>4.40, P<0.05)。在连锁不平衡分析中, 由2个(rs3750192和rs35201266)、3个(rs1877670、rs3750192和rs7009708)以及4个(rs1996147、rs1877670、rs3750192和rs7009708)SNPs位点构建的单倍型均显示与精神分裂症显著性关联(c²>7.10, 整体P<0.05)。总之, EGR3基因与中国汉族人群精神分裂症遗传易感性相关, 后续关于EGR3基因进一步的功能研究将会更好的帮助我们了解该基因在疾病病理学机制中的作用。

关键词: 单倍型, 精神分裂症, EGR3, 传递不平衡检验(TDT), SNP

Abstract: Previous studies showed that EGR3 gene located in chromosome 8p21.3 was involved in the etiology of schizophrenia. However, the finding failed to be replicated in several case-control studies. To investigate the genetic role of the EGR3 gene in Chinese psychiatric patients, we genotyped five single nucleotide polymorphisms (SNPs) in EGR3 gene locus using 93 nuclear families in Han Chinese, and performed transmission disequilibrium test (TDT). In this study, two SNPs (rs1996147 and rs3750192) showed significant association with schizophrenia (c²>4.40, P<0.05). In the linkage disequilibrium analysis, the significant association was also found in two- (rs3750192-rs35201266), three- (rs1877670- rs3750192-rs7009708) and four-SNP (rs1996147-rs1877670-rs3750192-rs7009708) tests of haplotype analyses (c²>7.10, global P<0.05). Overall, the results suggested that EGR3 gene may play an important role in schizophrenia suscep-tibility in the Han Chinese population, and further functional exploration of the EGR3 gene will contribute to the underlying molecular mechanism for schizophrenia pathogenesis.

Key words: schizophrenia, EGR3, transmission disequilibrium test, SNP, haplotype

宁启兰，马旭东，焦李子，牛晓蓉，李建鹏，王彬，张欢，马捷. 基于核心家系的EGR3基因与精神分裂症的关联研究[J]. 遗传, 2012, 34(3): 307-314.

NING Qi-Lan, MA Xu-Dong, JIAO Li-Zi, NIU Xiao-Rong, LI Jian-Peng, WANG Bin, ZHANG Huan, MA Jie. A family-based association study of the EGR3 gene polymorphisms and schizophrenia[J]. HEREDITAS, 2012, 34(3): 307-314.

参考文献

[1] International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sulli-van PF, Sklar P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 2009, 460(7256): 748-752.
[2] Zhong NN, Zhang R, Qiu C, Yan H, Valenzuela RK, Zhang H, Kang WH, Lu SM, Guo TW, Ma J. A novel replicated association between FXYD6 gene and schizophrenia. Biochem Bioph Res Co, 2011, 405(1): 118-121.
[3] 马捷, 樊金波, 吴胜男, 张长顺, 纪宝虎, 王磊, 李兴旺, 顾牛范, 冯国鄞, Clair DS, 贺林. 在亚洲和欧洲人群中对一个AC二核苷酸重复的多态性位点与精神分裂症的关联研究. 遗传, 2007, 29(10): 1207-1213.
[4] 李俊宁, 许琪, 沈岩, 季梁. 偏执型精神分裂症与4个涉及多巴胺代谢的基因之间的关联分析. 遗传, 2006, 28(4): 403-406.
[5] Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry, 2002, 7(4): 405-411.
[6] Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV, Brzustowicz LM, Kaufmann CA, Garver DL, Gurling HM, Helgason T. Genome scan meta-analysis of schizo-phrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet, 2003, 73(1): 34-48.
[7] O’Donovan MC, Williams NM, Owen MJ. Recent advances in the genetics of schizophrenia. Hum Mol Genet, 2003, 12(Suppl. 2): R125-R133.
[8] Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjorns-dottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Stefansson K. Neuregulin 1 and susceptibility to schizo-phrenia. Am J Hum Genet, 2002, 71(4): 877-892.
[9] Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M, Tonegawa S. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci USA, 2003, 100(15): 8993-8998.
[10] Yamada K, Gerber DJ, Iwayama Y, Ohnishi T, Ohba H, Toyota T, Aruga J, Minabe Y, Tonegawa S, Yoshikawa T. Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc Natl Acad Sci USA, 2007, 104(8): 2815-2820.
[11] Lohoff FW, Weller AE, Bloch PJ, Buono RJ, Doyle GA, Ferraro TN, Berrettini WH. Association between poly-morphisms in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) on chromosome 8p and schizophrenia. Neuropsychobiology, 2008, 57(1-2): 55-60.
[12] Tabarés-Seisdedos R, Rubenstein JLR. Chromosome 8p as a potential hub for developmental neuropsychiatric disor-ders: implications for schizophrenia, autism and cancer. Mol Psychiatry, 2009, 14(6): 563-589.
[13] Kim SH, Song JY, Joo EJ, Lee KY, Ahn YM, Kim YS. EGR3 as a potential susceptibility gene for schizophrenia in Korea. Am J Med Genet, 2009, 153B(7): 1355-1360.
[14] Lee SM, Vasishtha M, Prywes R. Activation and represssion of cellular immediate early genes by serum response factor cofactors. J Biol Chem, 2010, 285(29): 22036-22049.
[15] O'Donovan KJ, Tourtellotte WG, Millbrandt J, Baraban JM. The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience. Trends Neurosci, 1999, 22(4): 167-173.
[16] O'Donovan KJ, Levkovitz Y, Ahn D, Baraban JM. Func-tional comparison of Egr3 transcription factor isoforms: identification of an activation domain in the N-terminal segment absent from Egr3beta, a major isoform expressed in brain. J Neurochem, 2000, 75(4): 1352-1357.
[17] Liu BC, Zhang J, Wang L, Li XW, Wang Y, Ji J, Yang FP, Wan CL, Gao LH, Xu YF, Feng GY, He L, Zhao XZ, He G. No association between EGR gene family polymorphisms and schizophrenia in the Chinese population. Prog Neuro-psychopharmacol Biol Psychiatry, 2010, 34(3): 506-509.
[18] Kyogoku C, Yanagi M, Nishimura K, Sugiyama D, Morinobu A, Fukutake M, Maeda K, Shirakawa O, Kuno T, Kumagai S. Association of calcineurin A gamma subunit (PPP3CC) and early growth response 3 (EGR3) gene polymorphisms with susceptibility to schizophrenia in a Japanese population. Psychiatry Res, 2009, 185(1-2): 16-19.
[19] Ma J, Qin W, Wang XY, Guo TW, Bian L, Duan SW, Li XW, Zou FG, Fang YR, Fang JX, Feng GY, St Clair D, He L. Further evidence for the association between G72/G30 genes and schizophrenia in two ethnically distinct populations. Mol Psychiatry, 2006, 11(5): 479-487.
[20] Dudbridge F. Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered, 2008, 66(2): 87-98.
[21] Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinfor-matics, 2005, 21(2): 263-265.
[22] Zou FG, Li C, Duan SW, Zheng YL, Gu NF, Feng GY, Xing YL, Shi JG, He L. A family-based study of the asso-ciation between the G72/G30 genes and schizophrenia in the Chinese population. Schizophr Res, 2005, 73(2-3): 257-261.
[23] Li L, Yun SH, Keblesh J, Trommer BL, Xiong HG, Radu-lovic J, Tourtellotte WG. Egr3, a synaptic activity regu-lated transcription factor that is essential for learning and memory. Mol Cell Neurosci, 2007, 35(1): 76-88.
[24] Rusnak F, Mertz P. Calcineurin: form and function. Physiol Rev, 2000, 80(4): 1483-1521.
[25] Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng HK, Caron MG, Tonegawa S. Condi-tional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci USA, 2003, 100(15): 8987-8992.
[26] Yamagata K, Kaufmann WE, Lanahan A, Papapavlou M, Barnes CA, Andreasson KI, Worley PF. Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Egr1/zif268. Learn Mem, 1994, 1(2): 140-152.
[27] Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci, 2007, 8(6): 413-426.
[28] Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res, 1999, 33(6): 523-533.
[29] du Bois TM, Huang XF. Early brain development disruption from NMDA receptor hypofunction: relevance to schizophrenia. Brain Res Rev, 2007, 53(2): 260-270.
[30] Roberts DS, Hu YH, Lund IV, Brooks-Kayal AR, Russek SJ. Brain-derived neurotrophic factor (BDNF)-induced synthesis of early growth response factor 3 (Egr3) controls the levels of type A GABA receptor α4 subunits in hippo-campal neurons. J Biol Chem, 2006, 281(40): 29431-29435.
[31] Hippenmeyer S, Shneider NA, Birchmeier C, Burden SJ, Jessell TM, Arber S. A role for neuregulin1 signaling in muscle spindle differentiation. Neuron, 2002, 36(6): 1035-1049.
[32] Jacobson C, Duggan D, Fischbach G. Neuregulin induces the expression of transcription factors and myosin heavy chains typical of muscle spindles in cultured human muscle. Proc Natl Acad Sci USA, 2004, 101(33): 12218-12223.
[33] Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjorns-dottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgis-dottir B, Stefansson K. Neuregulin 1 and suscepti-bility to schizophrenia. Am J Hum Genet, 2002, 71(4): 877-892.
[34] Alaerts M, Ceulemans S, Forero D, Moens LN, De Zutter S, Heyrman L, Lenaerts AS, Norrback KF, De Rijk P, Nilsson LG, Goossens D, Adolfsson R, Del-Favero J. Support for NRG1 as a susceptibility factor for schizophrenia in a northern Swedish isolated population. Arch Gen Psychiatry, 2009, 66(8): 828-837.
[35] Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry, 2010, 15(12): 1176-1189.
[36] Guo AY, Sun JC, Jia PL, Zhao ZM. A Novel microRNA and transcription factor mediated regulatory network in schizophrenia. BMC Syst Biol, 2010, 4(1): 10.

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基于核心家系的EGR3基因与精神分裂症的关联研究

A family-based association study of the EGR3 gene polymorphisms and schizophrenia

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