心境障碍与5-羟色胺转运体基因的连锁不平衡(英文)

Linkage disequilibrium of serotonin transporter gene andmood disorders

背景:流行病学研究表明心境障碍具有明显的家族聚集性。在5-羟色胺系统中,由于5-羟色胺转运体多分布于中枢神经系统的突触前膜,在5-羟色胺重摄入突触前膜神经元的过程中起重要作用,因此,5-羟色胺功能系统的一些相关基因是心境障碍的候选基因。目的:探讨心境障碍与5-羟色胺转运体基因之间的分子遗传学联系。设计:采用成组设计方法,以患者及其父母所组成的核心家系为观察对象,把父母作为患者的“内对照”,通过传递/传递不平衡检验进行连锁不平衡分析。单位:汕头大学精神卫生中心,中山大学基础医学院,济宁医学院第二附属医院。对象:以2001-06/2002-06济宁医学院第二附属医院和汕头大学精神卫生中心住院和门诊心境障碍核心家系作为观察对象,均为中国汉族人。诊断符合美国精神障碍诊断与统计手册第4版心境障碍诊断标准。方法:所有被试者进行自编家系调查表,汉密顿抑郁、焦虑量表和Bech-Rafaelsen躁狂量表测试。然后进行基因组DNA制备,应用聚合酶链反应和限制性片段长度多态性分析方法,检测其5-羟色胺转运体基因中启动子区(5-HTTLPR)、第2内含子(VNTR)和3’端非编码区(3’UTRG/T)基因多态性,并进行连锁不平衡(TDT)分析。主要观察指标:5-羟色胺转运体基因3个位点等位基因以及3各位点组合的单体型与心境障碍之间的分子遗传学联系。结果:共收集完成72个家系,247人,选择其中适合遗传关联分析的72个核心家系的232人进行分析。5-羟色胺转运体基因中的VNTR与3’UTRG\T2个位点组合单倍型与心境障碍存在关联(TDT-χ2=4.08,经MonteCarlo逼真法1000次重复校正后的经验P值=0.04),其他各位点5-HTTLPR、VNTR、3’UTRG/T等位基因与心境障碍未发现存在连锁不平衡,其他位点组合的单体型分析也未发现存在连锁不平衡。结论:5-羟色胺转运体基因在心境障碍的遗传病因中可能起着一定作用。

BACKGROUND： Epidemiological studies have shown obvious familial aggregation of mood disorders. In serotonin system, serotonin transporter gene （5-HTF） is expressed mostly in the presynaptic membrane in the central nervous system, and plays an important role in serotonin reuptake into the presynaptic neurons. Therefore, some genes in relation to serotonin function are considered candidate genes for mood disorder susceptibility. OBJECTIVE： To examine the molecular genetic association between mood disorder and serotonin transporter gene. DESIGN： Group design method was used to observe the core families comprising the patients and their parents, with the parents serving as the internal control for analysis of linkage disequilibrium analysis by transmission/transmission disequilibrium test （TDT）. SETTING： Center of Mental Health of Shantou University, College of Basic Medical Science, Sun Yat-sen University, and Second Hospital Affiliated to Jining Medical College. PARTICIPANTS： Mood disorder core families were recruited from the inpatients and outpatients of Second Hospital Affiliated to Jining Medical College and Center of Mental Health of Shantou University between June 2001and June 2002. All of the subjects involved were Chinese of Han Nationality. The diagnosis was made in accordance to the diagnostic criteria described for mood disorders of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition （DSM-IV）. METHODS： Family survey was conducted using self-designed questionnaire, and all subjects underwent evaluation with Hamilton＇s Depression and Anxiety Scale and Bech-Rafaelsen Mania Scale. The genome DNA was obtained from all subjects for detecting of 5-HTT gene polymorphism in the promoter region （5-HTTLPR）, the second intron （VNTR） and 3＇non-coding region （3＇UTRG/T） using polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） analysis, and TDT was also conducted. MAIN OUTCOME MEASURES： Molecular genetic association of the 3 alleles and their combinations in haploids with mood disorder. RESULTS： Altogether 247 patients from 72 families were recruited, but only 232 patients from 72 core families were eligibal for heredity analysis. Two haploids with the combination of VNTR in 5-HTT gene and either of the 2 loci of 3＇UTRG／T were found to associate with mood disorder （X^2= 4.08 by TDT, empirical P value =0.04 after 1 000 corrections by Monte Carlo simulation method）, but no linkage disequilibrium was observed between 5-HTTLPR, VNTR, or 3＇ UTRG/T allele in tbe other loci and mood disorder, nor was the linkage found in the haploids with combination of other loci. CONCLUSION： 5-HTT gene might play a role in the genetic disposition of mood disorder.