Kim S-J, Cox N, Courchesne R, Lord C, Corsello C, Akshoomoff N, Guter S, Leventhal B L, Courchesne E, Cook E H
Laboratory of Developmental Neuroscience, Child and Adolescent Psychiatry, Department of Psychiatry MC3077, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Mol Psychiatry. 2002;7(3):278-88. doi: 10.1038/sj.mp.4001033.
The serotonin transporter gene (SLC6A4, MIM 182138) is a candidate gene in autistic disorder based on neurochemical, neuroendocrine studies and the efficacy of potent serotonin transporter inhibitors in reducing ritualistic behaviors and related aggression. An insertion/deletion polymorphism (5-HTTLPR) in the promoter region and a variable number of tandem repeat polymorphism (VNTR) in the second intron, were previously identified and suggested to modulate transcription. Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium. In the present study, TDT was conducted in 81 new trios. A previous finding of transmission disequilibrium between a haplotype consisting of the 5-HTTLPR and intron 2 VNTR was replicated in this study, but not preferential transmission of 5-HTTLPR as an independent marker. Because of inconsistent transmission of 5-HTTLPR across studies, SLC6A4 and its flanking regions were sequenced in 10 probands, followed by typing of 20 single nucleotide polymorphisms (SNPs) and seven simple sequence repeat (SSR) polymorphisms in 115 autism trios. When individual markers were analyzed by TDT, seven SNP markers and four SSR markers (six SNPs, 5-HTTLPR and the second intron VNTR from promoter 1A through intron 2 of SLC6A4, one SSR from intron 7 of SLC6A4, one SNP from the bleomycin hydrolase gene (BLMH, MIM 602403) and one SSR telomeric to BLMH) showed nominally significant evidence of transmission disequilibrium. Four markers showed stronger evidence of transmission disequilibrium (TDT(max) P = 0.0005) than 5-HTTLPR.
基于神经化学、神经内分泌研究以及强效血清素转运体抑制剂在减少仪式行为和相关攻击行为方面的疗效，血清素转运体基因（SLC6A4，MIM 182138）是自闭症谱系障碍的一个候选基因。此前已鉴定出该基因启动子区域的插入/缺失多态性（5-HTTLPR）和第二个内含子中的可变串联重复多态性（VNTR），并认为它们可调节转录。此前已对自闭症谱系障碍中的SLC6A4进行了六项基于家系的关联研究，其中四项研究显示名义上有显著的传递不平衡，两项研究没有名义上显著传递不平衡的证据。在本研究中，对81个新的三联体进行了传递不平衡检验（TDT）。本研究重复了此前关于由5-HTTLPR和内含子2 VNTR组成的单倍型之间传递不平衡的发现，但未发现5-HTTLPR作为独立标记的优先传递。由于5-HTTLPR在各项研究中的传递情况不一致，对10名先证者的SLC6A4及其侧翼区域进行了测序，随后在115个自闭症三联体中对20个单核苷酸多态性（SNP）和7个简单序列重复（SSR）多态性进行了分型。当通过TDT分析各个标记时，七个SNP标记和四个SSR标记（六个SNP、5-HTTLPR以及从SLC6A4启动子1A到内含子2的第二个内含子VNTR、一个来自SLC6A4内含子7的SSR、一个来自博来霉素水解酶基因（BLMH，MIM 602403）的SNP以及一个位于BLMH端粒的SSR）显示出名义上显著的传递不平衡证据。四个标记显示出比5-HTTLPR更强的传递不平衡证据（TDT(max) P = 0.0005）。
