International Journal of Psychiatry and Neurology
Vol.1 No.4(2012), Article ID:7131,5 pages DOI:10.12677/IJPN.2012.14009
Oppositional Defiant Disorder to Biological Research
1Second Affiliated Hospital of Xinxiang Medical, Xinxiang
2College of Pharmacy, Xinxiang Medical University, Xinxiang
Email: *bcd2009@126.com
Received: Jul. 25th, 2012; revised: Aug. 3rd, 2012; accepted: Aug. 15th, 2012
ABSTRACT：
This article provided an overview of Oppositional Defiant Disorder research progress of biological factors, from the epidemiological characteristics, the adverse factors during the pregnancy and prenatal period, and genetic research these three aspects, and believed that its development was closely related to genetic factors. Through genetic research could provide its susceptibility gene, which provided help for the prevention and treatment of diseases from a biological perspective.
Keywords: Oppositional Defiant Disorder; Biology; Gene; Review
对立违抗障碍生物学研究进展
王长虹1，宁秋芬1，刘 蒙1,2，王东平1，李 晏1*，杨 俊2*
1新乡医学院第二附属医院，新乡
2新乡医学院药学院，新乡
Email: *bcd2009@126.com
摘 要：
本文从流行病学特征、母孕期和围生期的不利因素、遗传学研究三方面概述了对立违抗障碍的生物学因素研究进展，并认为其发生发展与遗传因素密切相关，通过基因研究可以提供其易感基因，从而从生物学角度为疾病的预防和治疗提供帮助。
收稿日期：2012年7月25日；修回日期：2012年8月3日；录用日期：2012年8月15日
关键词：对立违抗障碍；生物学；基因；综述
1. 引言
对立违抗障碍(oppositional defiant disorder，ODD)属于破坏性行为障碍，是儿童青少年精神科门诊及儿童心理门诊常见疾病。其主要以对抗、消极抵抗、易激惹和敌对等行为为基本特征。是儿童期尤其是学龄期常见的行为障碍，其常导致儿童学业不佳、社交不良，严重时可影响儿童的身心健康和社会适应，其中部分患者如果没能及时发现并治疗，任其发展可转化为品行障碍(conduct disorder, CD)，甚至是反社会性人格障碍(antisocial personality disorder, APD)，因而也就引起家长、学校和社会各界的广泛关注，同时也成为了儿童心理卫生领域研究的热点。所以寻找其致病影响因素进而采取干预措施变得尤为重要。鉴于ODD、CD、注意缺陷与多动障碍(attention-deficit/hyperactivity disorder, ADHD)、物质滥用及情感障碍发病有一定的家族聚集倾向，很多学者认为生物学因素在ODD的发病过程中起到很关键的作用。所以本文就对ODD发病过程中的生物学因素做一综述。至于心理社会因素方面的影响国内外已有很多文献述及，在此就不再赘述。
2. 正文
2.1. 流行病学研究
ODD最先出现在美国的DSM-III-R[1]中，但对于ODD的研究却起步较晚，国内的研究也只是最近十年。其发病率国内外的文献均有述及。但报道尚缺乏一致性。可能与不同的国家、地域、生活文化背景、社会经济背景、性格特征、性别年龄以及家庭生长环境、评估方法等因素有关。
2001年我国的孙凌、苏林雁等[2]人在长沙市的中小学中进行调查，结果发现ODD患病率为8%，其中女性为5%，男性为11%。而根据DSM-IV的诊断标准，经流行病调查及现场测试，国外报道的社区患病率为6%，总体徘徊在2%~16%之间，其中8~10岁为高峰年龄，随着年龄增长逐渐下降(11~12岁患病率为2.3%，13~15岁患病率为1.4%)[3]。1996年Cohen和Zoccolillo[4]研究发现青春期前女孩患病率为3%，青春期女孩为8%。而这同年龄组的男孩患病率却均为7%，此项研究表明了女孩在进入青春期后患病率呈逐渐上升的趋势。2004年Canino G.等[5]人在Puterto Rico随机抽取4~17岁孩子1886名，结果发现ODD患病率为5.5%。同一年Ersan E.E.[6]等人在Sivas province center的8个中小学中随机选取了1425名6~15岁学生，发现ODD患病率为11.5%，男孩的患病率高于女孩。
从以上调查不难看出，普遍观点认为在青春期前男孩患病率是高于女孩的，至于青春期后就没有什么区别了。
其实ODD常合并CD、ADHD，APD等存在。从以下调查中我们也不难看出。国外报道显示ADHD合并ODD为54%~93%不等，而ODD合并ADHD的为35%~64%[7]。国内调查发现ODD合并ADHD为51%[8]。
2.2. 生物学因素
众所周知，儿童青少年的行为问题分为外向性行为问题和内向性行为问题，外向性行为问题包括，注意缺陷与多动障碍、违纪、攻击、反社会行为等；内向性行为问题，如焦虑、抑郁和退缩等。而ODD患儿的临床表现主要以外化行为为主，总之无论是外化行为还是内化行为亦或是儿童的心理变化其发生的物质基础都与神经系统有关，特别是中枢神经系统。而神经系统的发育及生理生化功能又受遗传因素调控。因此，近年来对于ODD遗传方面的研究就备受各国专家的关注。
2.2.1. 母孕期和围生期的不利因素
母孕期、围生期出现的各种不利因素都可能造成ODD儿童患病重要的生物学危险因子。孕期危险因素比如：母孕期患严重疾病或者服用药物、接触放射线或某些毒性物质、心理压力大、营养状况差、精神受刺激、孕妇吸烟或被动吸烟以及母亲受孕时父亲大量饮酒等。此类因素都可以引起孕妇体内儿茶酚胺分泌过度，从而导致胎儿神经系统发育不良，造成儿童的外化行为，从而也就为ODD的发病埋下隐患。另外围生期出现的胎动厉害、早产、过期产或难产、缺氧窒息等也均可影响儿童神经发育，尤其是脑的发育迟缓，也同样是产后儿童行为问题的危险因素。Kahn R.S.等[9]发现产前母亲吸烟的ODD患儿并属DAT(多巴胺转运体)+/+基因型，这些孩子的对立行为分数明显升高。而只有产前母亲吸烟史或DAT+/+基因型的儿童，对立行为分数没有明显升高。Pargan等[10]则研究发现，母亲分娩时年龄过小，日后其孩子更容易就出现攻击行为；而随着产妇随着年龄的不断增大，儿童的这种行为问题便会呈下降趋势，特别是多动、违纪、攻击等外化行为问题有明显的减少。Mccormicck等[11]研究显示，儿童低出生体重比正常出生体重的更容易出现行为问题。但是国外有一项关于基因与犯罪的研究却发现，犯罪与生育年龄过大导致的基因突变有关[12]。当然也有人发现，在矫正机构的犯罪人员中，37%的人有围生期障碍史；在新生儿期曾有过新生儿窒息或新生儿疾病的未成年人犯罪的危险度增加。
2.2.2. 遗传因素
Jaffee等[13]人研究显示，在儿童行为问题的发生中，遗传因素所起的作用占62.6%，环境占29.2%，家庭暴力占8%，从此项研究中不难看出遗传因素的重要性。Nelson等[14,15]人对5-HT1B受体基因和MAOA基因的分子遗传学进行研究发现，此类基因的多态性与攻击和冲动行为有关。2002年Holmes A.等[16]人则发现5-HTT基因剔除鼠，由于5-HT1A/1B功能的丧失而使其攻击性明显降低，但是2000年Preuss U.W.等[17]人的研究则并未证明5-HTT基因多态性与行为障碍存在关联。同一年，Comings D.E.等[18]发现DA基因、5-HT基因、NE基因等神经递质基因在ODD、ADHD、CD外向性行为中扮演重要角色。由于ODD、CD、ADHD常常伴发，所以就有人认为它们可能共享一个基因或者分享大部分基因，而ODD只是其中的一种基因表现型[19,20]。Eaves-L.[21]对双生子的调查发现ODD比ADHD显示更高的遗传性，但是没能证明ODD基因遗传的独立性。苏林雁等[22]研究认为，ADHD与ODD合并患者，存在5-HT功能低下，并认为5-HT功能低下与儿童攻击、冲动行为存在关联。Kirley等[23]也发现ODD患者前额叶皮层功能发生异常，5-HT、DA、NE递质系统的功能有变化。我国苏林雁等人[22]通过对61个患者(33个ADHD患者，28个ODD合并ADHD患者)的研究发现，合并组的血清5-HT浓度低于ADHD组。由此我们可以推论：5-HT系统功能是儿童冲动行为的生物学标记。而冲动行为恰是ODD患儿的重要特征，近年来有许多研究结果[24-28]也表明5-HT作为一种神经递质，与一系列的行为表现有关，比如自杀、攻击性、酒精依赖、营养摄入、记忆能力、焦虑症、情绪障碍、自闭症和强迫障碍等[29]。其实研究结果重复率比较高的结论之一就是5-HT功能降低可导致冲动、攻击和其他脱抑制行为，但此结论的获得主要来自于对成年人人格障碍[30]、物质依赖[31]和其他以行为脱抑制为特点的疾病的研究[32]。
由以上研究我们可以发现5-HT基因、DA基因、NE基因在ODD、CD、ADHD外向行为中起到关键作用，所以也就普遍认为ODD的发病5-HT、DA、NE有关，尤其是5-HT，其含量的改变直接影响行为的变化。所以与5-HT合成、转运、降解有关的色氨酸羟化酶(TPH)基因、五羟色胺转运体(5-HTT)基因、单胺氧化酶(MAO)基因就成为了研究的热点。
色氨酸羟化酶(TPH)是5-HT合成过程中的关键限速酶，其变化会直接影响到体内5-HT的合成，从而影响其功能，因而编码TPH的基因多态性就可能影响到与5-HT有关的一些行为表现[33]。近年来有研究发现[34,35]TPH基因敲除鼠的脑内神经元5-HT浓度保持正常水平，而外周组织的含量却明显降低。这就提示TPH存在同工酶(TPH1，TPH2)。通过动物实验已经证实TPH1存在于外周，而TPH2存在于中枢[36]，控制脑内5-HT合成。TPH2基因在人脑中对5-HT的调控起到关键作用，从而影响人类的内化行为和外化行为。国内外对TPH2基因单核苷酸多态性与自杀行为及抑郁症的关系研究均有报道[37-39]。当然其与ADHD[40,41]，孤独症[42]和双相情感障碍[43]的关系研究也有报道。但对于TPH基因与ODD的发病是否存在关联还没有相关的文献报道，ODD是否也共享了此基因，有待进一步研究证实。
5-HTT是5-HT神经递质传递中的关键角色，其基因存在2个重要的多态性。第1个多态性在第2个内含子，它是这3个突变遗传因子的可变数目串联重复序列(VNTR)。第2个多态性在启动子区域，5-HT转运体链接多态性区域(5-HTTLPR)，有两个突变遗传因子，即L和S的44个碱基对的插入缺失。此两个等位基因分别位于：短等位基因(S, 484 bp)及长等位基因(L, 528 bp)。5-HTT基因多态性，尤其是携带短等位基因SS的个体，与个体寻找新奇性有关[44]。Tom Fowlera等[45]人发现在ADHD青少年中编码5-HTT及两个降解酶的基因发生变异，MAOA和COMT与精神病特征中的情绪功能紊乱有关。2000年Friseh A.[46]等人发现5-HTTLPR对5-HT系统的功能有重要调节作用，短等位基因活性较低，且和多种精神障碍及人格特质存在关联。次年，Danielle L.S.[47]等则研究发现5-HTTLPR的LL基因型可能使Alzheimer病人发生攻击行为的风险增加。2007年Li D.等[48]人发现5-HTT基因多态性与自杀行为的发病机理有关。但Galina Pungercica等[49]人的研究却未能坚持5-HTTLPR与自杀行为存在关联。Snoek H.等[50]人对13名ODD + ADHD儿童和7名ODD儿童与15名正常组儿童分别注入5-HT(1B/1D)激动剂舒马曲坦(5-HT1受体激动药)后，结果显示：ODD儿童的生长激素反应显著增强。经舒马曲坦注射过的正常对照组儿童表现出激素水平的显著增高，但ODD组并无此表现。从而得出，ODD儿童的突触后5-HT(1B/1D)转运体更加敏感的结论。但Grevet E.H.[51]的研究却与之相反。他发现5-HTTLPR的多态性与ADHD并无相关性。携带S等位基因的患者注意缺陷和新奇探险的分值增高，出现药物依赖的频率增高，但是在校正后的多重对比中这些差别未能重复，说明S等位基因不是ADHD的直接相关因素，可能和ADHD的行为内在表型有关。
MAO是单胺类神经递质重要的代谢酶，存在两种形式(MAOA, MAOB)其中MAOA主要代谢NE和5-HT，所以MAOA与5-HT的亲和力高于MAOB。关于这两种亚型来自对基因敲除动物的研究[52,53]。2008年Biederman J.[54]发现ADHD与MAOA基因存在关联，随后国外的Manor I.，Katharine D.等[55,56]人又分别论证了MAOA与ADHD连锁。Craiq I.W.[57]发现MAOA基因的变异型与反社会性人格和攻击行为有关。Malmberg K等人[58]研究了ADHD/DBD的显性量与血小板中的MAOB活性的关联性，并研究了两个5-HT能基因的多态性，分别为MAOA的串联重复多态性(MAOA-VNTR)和5-HTT的基因启动子区多态性。结果发现女孩的血小板低MAOB活性与ODD的症状相关，对于男孩，MAOA的短串联重复序列等位基因与破坏行为有关。
Li J.，Kanq C.等[59]人发现MAOA基因多态性与青少年ADHD的发病存在关联。两年后Guan L.等[60]人证实了这一结论。2011年Riti I.M.等[61]人研究发现在没有受过躯体虐待的白人中高活性的MAOA基因对反社会性人格起保护作用，从而为MAOA表达和反社会性行为之间的联系提供了支持。Esther J.M.等[62]人研究发现在严重受虐待孩子中MAOA高活性不可能对虐待带来的影响起保护作用，但可能增加外化行为(反社会和攻击行为)的危险性。Prom-Wormley等[63]人发现MAOA基因和童年逆境可能共同构成女性患品行障碍的危险因素。
2.3. 存在的问题和展望
以ADHD、ODD、CD为主的行为障碍是一类共享多基因疾病。现在的研究主要是通过同时检测多个候选基因来完成此类障碍的遗传学研究。但是国内外个研究结果存在些许差异，这可能与样本量大小、入组标准以及其他的一些不确定因素有关，有待以后的研究增大样本量，来进一步核实。对于ODD来讲单独的研究还没有其与TPH基因、5-HTT基因及MAOA基因存在关联的报道。有待以后的学者对此方面做些研究，发现其易感基因，以对ODD的生物学发病机制有更深的了解，从而为临床的诊断和治疗做出贡献。
3. 致谢
本研究分别受到河南省医学科技攻关资助项目(编号：200570)；新乡医学院高层次人才科研资助项目(编号：08BSKYQD-004)；河南省科技攻关计划项目(编号：112102310211)以及新乡医学院精神药物重点实验室的大力支持。
参考文献 (References)
[1] D. M. Fergusson, L. J. Horwood and M. T. Lynskey. Structure of DSM-Ⅲ-R criteria for disruptive childhood behaviors: Confirmatory factor models. Journal of the American Academy of Child and Adolescent Psychiatry, 1994, 33: 1145.
[2] 孙凌, 苏林雁. 长沙市中小学生对立违抗性障碍的现况及对照研究[J]. 中华精神科杂志, 2001, 34(4): 208-211.
[3] T. Ford, R. Goodman and H. Meltzer. The British child and adolescent mental health survey 1999: The prevalence of DSM-IV disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 2003, 42(10): 1203-1211.
[4] M. Zoccolillo, R. Tremblay and F. Vitaro. DSM-III-R and DSMIII criteria for conduct disorder in preadolescent girls: Specific but insensitive. Journal of the American Academy of Child and Adolescent Psychiatry, 1996, 35(4): 461-470.
[5] G. Canino, P. E. Shrout, M. Rubio-Stipec, et al. The DSM-IV rates of child and adolescent disorders in Puerto Rico: Prevalence, correlates, service use and the effects of impairment. Archives of General Psychiatry, 2004, 61(1): 85-93.
[6] E. E. Ersan, O. Dogan, S. Dogan, et al. The distribution of symptoms of attention-deficit/hyperactivity disorder and opposetional defiant disorder in school age children in Turkey. European Child & Adolescent Psychiatry, 2004, 13(6): 354-361.
[7] P. S. Jensen, D. Martin and D. P. Cantwell. Comorbidity in ADHD implication for research. Practice and DSM-IV. Journal of the American Academy of Child and Adolescent Psychiatry, 1997, 36: 1065-1079.
[8] 孙凌, 苏林雁, 刘永忠. 长沙市中小学生对立违抗障碍的现况及对照研究[J]. 中华精神科杂志, 2001, 34(4): 208-211.
[9] R. S. Kahn, J. Khoury, W. C. Nichols, et al. Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. Journal of Pediatrics, 2003, 143(1): 104-110.
[10] L. Paqani, B. Boulerice, R. E. Tremblay, et al. Behavioural development in children of divorce and remarriage. Journal of Child Psychology and Psychiatry, 1997, 38((7): 769-781.
[11] M. C. McCormick, K. Workman-Daniels and J. Brooks-Gunn. The behavioral and emotional wellbeing of school-age children with different birth weights. Pediatrics, 1996, 97(1): 18-25.
[12] M. Wasserman, L. David, B. Wachbroit, et al. Genetics and criminal behavior. Cambridge: Cambridge University Press, 2001: 335.
[13] S. R. Jaffee, T. E. Moffitt, A. Caspi, et al. Influence of adult domestic violence on children’s internalizing and externalizing problems: An environmentally informative twin study. Journal of the American Academy of Child and Adolescent Psychiatry, 2002, 41(9): 1095-1103.
[14] R. J. Nelson, S. Chiavegatto. Molecular basis of aggression. Trends in Neurosciences, 2001, 24(12): 713-719.
[15] S. B. Manuck, J. D. Flory, R. E. Ferrell, et al. A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression impulsivity and central nervous system serotonergic responsivity. Psychiatry Research, 2000, 24(1): 9-23.
[16] A. Holmes, D. L. Murphy and J. N. Crawley. Reduced aggression in mice lacking the serotonin transporter. Psychopharmacology, 2002, 161(2): 160-167.
[17] U. W. Preuss, M. Soyka, M. Bahlmann, et al. Serotonin transporter gene regulatory region polymorphism (5-HTTLPR), [3H] paroxetine binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity. Psychiatry Research, 2000, 96(1): 51-61.
[18] D. E. Comings, R. Gade-Andavolu, N. Gonzalez, et al. Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder. Clinical Genetics, 2000, 58(1): 31-40.
[19] D. E. Comings, R. Gade-Andavolu, N. Gonzalez, et al. Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: Multivariate regression analysis of 20 genes. Clinical Genetics, 2000, 57(3): 178-196.
[20] F. L. Coolidge, L. L. Thede and S. E. Young. Heritability and the comorbidity of attention deficit hyperactivity disorder with behavioral disorders and executive function deficits: A preliminary investigation. Developmental Neuropsychology, 2000, 17(3): 273-287.
[21] L. Eaves, M. Rutter, J. L. Silberg, et al. Genetic and environmental causes of covariation in interview assessments of disrupttive behavior in child and adolescent twins. Behavior Genetics, 2000, 30(4): 321-334.
[22] 苏林雁, 谢光荣, 高雪屏等. 注意缺陷多动障碍合并对立违抗性障碍患儿血清5羟色胺的对照研究[J]. 中华精神科杂志, 2001, 34(4): 230.
[23] A. Kirley, N. Lowe, C. Mullins, et al. Phenotype studies of the DRD4 gene polymorphisms in ADHD: Association with opposetionaldefiant disorder and positive family history. American Journal of Medical Genetics Part B: Neuropsychiatric, 2004, 131B(1): 38-42.
[24] R. K. McHugh, S. G. Hofmann, A. Asnaani, et al. The serotonin transporter gene and risk for alcohol dependence: A meta-analytic review. Drug and Alcohol Dependence, 2010, 108(1-2): 1-6.
[25] J. E. Pirkis, P. M. Burgess, A. K. Johnston, et al. Use of selective serotonin reuptake inhibitors and suicidal ideation: findings from the 2007 National Survey of Mental Health and Wellbeing. Medicine, 2010. 192(1): 53.
[26] N. Nordquist, L. Oreland. Serotonin, genetic variability, behaveiour, and psychiatric disorders: A review. Medical Science, 2010, 115(1): 2-10.
[27] E. H. Kang, H. B. Shim, K. J. Kim, et al. Platelet serotonin transporter function after short-term paroxetine treatment in patients with panic disorder. Psychiatry Research, 2010, 176(2-3): 250-253.
[28] F. F. Rocha, L. A. Marco, M. A. Romano-Silva, et al. Obsessivecompulsive disorder and 5-HTTLPR. Revista Brasileira de Psiquiatria, 2009, 31(3): 287-288.
[29] D. I. Zafeiriou, A. Ververi and E. Vargiami. The serotonergic system: Its role in pathogenesis and early developmental treatment of autism. Current Neuropharmacology, 2009, 7(2): 150-157.
[30] D. Marazziti, S. Baroni, I. Masala, et al. Impulsivity, gender, and the platelet serotonin transporter in healthy subjects. Journal of Neuropsychiatric Disease and Treatment, 2010, 6: 9-15.
[31] J. A. Brewer, M. N. Potenza, et al. The neurobiology and genetics of impulse control disorders: Relationships to drug addictions. Biochemical Pharmacology, 2008, 75(1): 63-65.
[32] E. F. Coccaro, R. Lee. Cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid: Reciprocal relationships with impulsive aggression in human subjects. Neural Transmission, 2010, 117(2): 241-248.
[33] H. K. Yoon, Y. K. Kim. Association between serotonin-related gene polymorphisms and suicidal behavior in depressive patients. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2008, 32(5): 1293-1297.
[34] D. J. Walther, J. U. Peter, S. Bashammakh, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science, 2003, 299(5603): 76.
[35] D. J. Walther, M. Bader. A unique central tryptophan hydroxyllase isoform. Biochemical Pharmacology, 2003, 66(9): 1673- 1680.
[36] X. Zhang, J. M. Beaulieu, T. D. Sotnikova, et al. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science, 2004, 305(5681): 217.
[37] P. Zill, U. W. Preuss, G. Koller, et al. SNP and haplotype analysis of the tryptophan hydroxylase 2 gene in alcohol-dependent patients and alcohol-related suicide. Neuropsychopharmacology, 2007, 32: 1687-1694.
[38] C. L. de Lara, J. Brezo, G. Rouleau, et al. Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression. Biological Psychiatry, 2007, 62: 72-80.
[39] H. K. Yoon, Y. K. Kim. TPH2-703G/T SNP may have important effect on susceptibility to suicidal behavior in major depression. Prog Neuropsychopharmacol Biological Psychiatry, 2009, 33(3): 403-409.
[40] T, Banaschewski, K, Becker, S, Scherag, et al. Molecular genetics of attention deficit/hyperactivity disorder: An overview. European Child & Adolescent Psychiatry, 2010, 19(3): 237-257.
[41] R. D. Oades, S. J. Lasky, H. Christiansen, et al. The influence of serotoninand other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis. Behavioral and Brain Functions, 2008, 4: 48.
[42] R. Sacco, V. Papaleo, J. Hager, et al. Case-control and familybased association studies of candidate genes in autistic disorder and its endophenotypes: TPH2 and GLO1. BMC Medical Genetics, 2007, 8: 11.
[43] S. B. Campos, D. M. Miranda, B. R. Souza, et al. Association of polymorphisms of the tryptophan hydroxylase 2 gene with risk for bipolar disorder or suicidal behavior. Journal of Psychiatric Research, 2010, 44(5): 271-274.
[44] R. Y. Ha, K. Namkoong, J. I. Kang, et al. Interaction between serotonin transporter promoter and dopamine receptor D4 polymorphisms on decision making. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2009, 33(7): 1217-1222.
[45] T. Fowlera, K. Langleya, et al. Psychopathy trait scores in adolescents with childhood ADHD: The contribution of genotypes affecting MAOA, 5HTT and COMT activity. Psychiatric Genetics, 2009, 19(6): 312-319.
[46] A. Friseh, B. Finkel and E. Michaelovsky. A rare short allele of the Serotonin transporter Promoter region (5-HTTLPR) found in an aggressive schiz-ophrenic patient of Jewish Libyan origin. Psychiatric Genetics, 2000, 10(4): 179-183.
[47] L. S. Danielle, B. G. Pollock, A. S. Robert, et al. The 5- HTTPR*S/*L polymorphism and aggressive behavior in Alzheimer disease. Archives of Neurology, 2001, 58(9): 1425-1428.
[48] D. Li, L. He. Meta-analysis supports association between serotonin transporter (5-HTT) and suicidal behavior. Molecular Psychiatry, 2007, 12(1): 47-54.
[49] G. Pungercica, A. Videtica, et al. Serotonin transporter gene promoter (5-HTTLPR) and intron 2(VNTR) polymorphisms: A study on Slovenian population of suicide victims. Psychiatric Genetics, 2006, 16: 187-191.
[50] H. Snoek, S. H. van Goozen, W. Matthys, et al. Serotonergic functioning in children with oppositional defiant disorder: A sumatriptan challenge study. Biological Psychiatry, 2002, 51(4): 319-325.
[51] E. H. Grevet, F. Z. Marques, C. A. Salgado, et al. Serotonin transporter gene polymorphism and the phenotypic heterogeneity of adult ADHD. Neural Transmission, 2007, 114(12): 1631- 1636.
[52] O. Cases, I. Seif, P. Gaspar, et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science, 1995, 268: 1763-1766.
[53] M. K. Lai, S. W. Tsang, P. T. Francis, et al. Reduced serotonin 5-HT2A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease. Brain Research, 2003, 974: 82-87.
[54] J. Biederman, J. W. Kim, A. E. Doyle, et al. Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: A preliminary study. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008, 147B(8): 1511-1518.
[55] I. Manor, S. Tyano, E. Mel, J. Eisenberg, et al. Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder(ADHD): Preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA). Molecular Psychiatry, 2002, 7(6): 626-632.
[56] D. Katharine, S. Karen, L. Naomi, et al. Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) is an Irish sample; preferential transmission of the MAO-A941G allele to affected children. Journal of Medical Genetics, 2005, 134B(1): 110-114.
[57] I. W. Craiq. The importance of stress and genetic variation in human aggression. Bioessays, 2007, 29(3): 227-236.
[58] K. Malmberg, H. L. Wargelius, P. Lichtenstein, et al. ADHD and disruptive behavior scores—associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents. Psychiatry, 2008, 23: 8-28.
[59] J. Li, C. Kanq, H. Zhang, et al. Monoamine oxidase A gene polymorphism predicts adolescent outcome of attention-deficit/ hyperactivity disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2007, 144B(4): 430-433
[60] L. Guan, B. Wanq, et al. A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: Suggesting multiple susceptibility genes among Chinese Han population. Molecular Psychiatry, 2009, 14(5): 546-554.
[61] I. M. Reti, J. Yanofski, et al. Monoamine oxidase A regulates antisocial personality in whites with no history of physical abuse. Comprehensive Psychiatry, 2011, 52(2): 188-194.
[62] J. M. Esther, B. A. vander Vegta, et al. High activity of monoamine oxidase A is associated with externalizing behaviour in maltreated and nonmaltreated adoptees. Psychiatric Genetics, 2009, 19(4): 209-211.
[63] E. C. Prom-Wormley, L. J. Eaves, et al. Monoamine oxidase A and childhood adversity as risk factors for conduct disorder in females. Psychological Medicine, 2009, 39(4): 579-590.
NOTES
*共同通讯作者。