Hu Xian-Zhang, Lipsky Robert H, Zhu Guanshan, Akhtar Longina A, Taubman Julie, Greenberg Benjamin D, Xu Ke, Arnold Paul D, Richter Margaret A, Kennedy James L, Murphy Dennis L, Goldman David
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD.
Butler Hospital, Brown University School of Medicine, Providence; Department of Psychiatry, Brown University School of Medicine, Providence.
Am J Hum Genet. 2006 May;78(5):815-826. doi: 10.1086/503850. Epub 2006 Mar 28.
A functional serotonin transporter promoter polymorphism, HTTLPR, alters the risk of disease as well as brain morphometry and function. Here, we show that HTTLPR is functionally triallelic. The L(G) allele, which is the L allele with a common G substitution, creates a functional AP2 transcription-factor binding site. Expression assays in 62 lymphoblastoid cell lines representing the six genotypes and in transfected raphe-derived cells showed codominant allele action and low, nearly equivalent expression for the S and L(G) alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function L(A)L(A) genotype was approximately twice as common in 169 whites with obsessive-compulsive disorder (OCD) than in 253 ethnically matched controls. We performed a replication study in 175 trios consisting of probands with OCD and their parents. The L(A) allele was twofold overtransmitted to the patients with OCD. The HTTLPR L(A)L(A) genotype exerts a moderate (1.8-fold) effect on risk of OCD, which crystallizes the evidence that the HTT gene has a role in OCD.
一种功能性血清素转运体启动子多态性，即5-HTTLPR，会改变疾病风险以及大脑形态学和功能。在此，我们表明5-HTTLPR在功能上是三等位基因的。L(G)等位基因，即带有常见G替换的L等位基因，会产生一个功能性AP2转录因子结合位点。在代表六种基因型的62个淋巴母细胞系以及转染的中缝核衍生细胞中进行的表达分析显示了共显性等位基因作用，并且S和L(G)等位基因的表达较低且几乎相等，这在5-HTT表达中占有的变异比之前认识到的更多。在169名患有强迫症（OCD）的白人中，功能获得性L(A)L(A)基因型出现的频率约为253名种族匹配对照的两倍。我们在由OCD先证者及其父母组成的175个三联体中进行了一项重复研究。L(A)等位基因向OCD患者的传递率高出两倍。5-HTTLPR L(A)L(A)基因型对OCD风险有中度（1.8倍）影响，这明确了5-HTT基因在OCD中起作用的证据。
