Furlong R A, Ho L, Walsh C, Rubinsztein J S, Jain S, Paykel E S, Easton D F, Rubinsztein D C
Department of Medical Genetics, Addenbrooke's Hospital, Cambridge, United Kingdom.
Am J Med Genet. 1998 Feb 7;81(1):58-63.
The serotonin transporter is a compelling candidate gene to examine in bipolar and unipolar affective disorder, since drugs that specifically inhibit the serotonin transporter can successfully treat depression. Previous association studies of a VNTR polymorphism in intron 2 and a functional insertion/deletion polymorphism in the promoter of this gene have produced conflicting results. The present study examined allele and genotype frequencies for both of these polymorphisms and resulting haplotypes in 87 English Caucasian bipolar patients, 125 English Caucasian unipolar affective disorder patients, and 174 controls. No significant associations were detected when these unipolar or bipolar cases were compared either separately or as a pooled "affective disorder" group to the controls. A meta-analysis of over 1,400 individuals of European Caucasian origin was then performed, comprising 772 controls, 375 bipolar and 299 unipolar patients for the VNTR polymorphism, and 739 controls, 392 bipolar and 275 unipolar patients for the promoter polymorphism. A significant association of promoter allele 2 was shown with bipolar (estimated odds ratio 1.21; 95% confidence interval 1.00-1.45), unipolar (OR 1.23; 95% CI 1.01-1.42), and combined bipolar + unipolar groups (OR 1.22; 95% CI 1.04-1.42). There was no demonstrable allelic association of the VNTR polymorphism with affective disorder: for the combined bipolar + unipolar group the odds ratios for VNTR alleles 9 and 10, compared with the common allele 12 were 1.05 (95% CI 0.56-1.95) and 0.90 (95% CI 0.77-1.05). These results suggest that the promoter allele 2, which has previously been shown to result in lower levels of serotonin transporter transcription, may be associated with affective disorder risk.
血清素转运体是双相情感障碍和单相情感障碍研究中一个极具吸引力的候选基因，因为特异性抑制血清素转运体的药物能够成功治疗抑郁症。此前关于该基因内含子2中VNTR多态性以及启动子区域功能性插入/缺失多态性的关联研究结果相互矛盾。本研究检测了87名英国白种人双相情感障碍患者、125名英国白种人单相情感障碍患者以及174名对照者中这两种多态性的等位基因和基因型频率，以及由此产生的单倍型。当将这些单相或双相情感障碍病例单独或作为一个合并的“情感障碍”组与对照组进行比较时，未发现显著关联。随后对1400多名欧洲白种人进行了荟萃分析，其中包括772名对照者、375名双相情感障碍患者和299名单相情感障碍患者用于VNTR多态性分析，以及739名对照者、392名双相情感障碍患者和275名单相情感障碍患者用于启动子多态性分析。结果显示，启动子2等位基因与双相情感障碍（估计比值比1.21；95%置信区间1.00 - 1.45）、单相情感障碍（比值比1.23；95%置信区间1.01 - 1.42）以及双相 + 单相合并组（比值比1.22；95%置信区间1.04 - 1.42）存在显著关联。VNTR多态性与情感障碍无明显等位基因关联：对于双相 + 单相合并组，与常见等位基因12相比，VNTR等位基因9和10的比值比分别为1.05（95%置信区间0.56 - 1.95）和0.90（95%置信区间0.77 - 1.05）。这些结果表明，此前已证明会导致血清素转运体转录水平降低的启动子2等位基因，可能与情感障碍风险相关。
