Collier D A, Stöber G, Li T, Heils A, Catalano M, Di Bella D, Arranz M J, Murray R M, Vallada H P, Bengel D, Müller C R, Roberts G W, Smeraldi E, Kirov G, Sham P, Lesch K P
Department of Psychological Medicine, Institute of Psychiatry, London, UK.
Mol Psychiatry. 1996 Dec;1(6):453-60.
The serotonin transporter (5-HTT) is a candidate locus for aetiological involvement in affective disorders. Biochemical studies in suicides and depressed patients suggest that 5-HT uptake function is frequently reduced in affective illness. Furthermore, 5-HTT is targeted by widely used antidepressant drugs such as fluoxetine. We have performed an association study of a short variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which restricts transcriptional activity of the 5-HTT promoter leading to low functional expression of the 5-HTT, in 454 patients with bipolar or unipolar affective disorder and 570 controls, derived from three European Centres (London, Milan and Würzburg). In all three centres, the frequency of the low activity allele was higher in patients than in controls (50% vs 45% in London, 45% vs 43% in Milan, 47% vs 40% in Würzburg). Although these differences were not individually significant, a stratified analysis of all three samples gave a significant overall odds ratio of 1.23 (95% confidence interval 1.02-1.49, P = 0.03). The excess of the homozygous low-activity genotype among the patients was even greater (odds ratio 1.53, 95% confidence interval 1.04-2.23, P = 0.02), suggesting partial recessively of the low-activity allele. Given the functional role of 5-HTT, our findings suggest that 5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders. If this finding is replicated, further work on genetic variants with low 5-HTT activity may facilitate the differential diagnosis of affective disorders, the assessment of suicidal behaviour, and the prediction of good clinical response to antidepressants.
血清素转运体（5-HTT）是情感障碍病因学中的一个候选基因位点。对自杀者和抑郁症患者的生化研究表明，情感疾病中5-羟色胺摄取功能常常降低。此外，5-HTT是广泛使用的抗抑郁药物如氟西汀的作用靶点。我们对5-HTT连锁多态性区域（5-HTTLPR）的一个短变体进行了关联研究，该变体限制5-HTT启动子的转录活性，导致5-HTT功能表达降低。研究对象来自三个欧洲中心（伦敦、米兰和维尔茨堡）的454例双相或单相情感障碍患者和570例对照。在所有三个中心，患者中低活性等位基因的频率均高于对照（伦敦为50%对45%，米兰为45%对43%，维尔茨堡为47%对40%）。虽然这些差异单独来看并不显著，但对所有三个样本进行分层分析得到的总体优势比为1.23（95%置信区间1.02 - 1.49，P = 0.03）。患者中纯合低活性基因型的过量更为明显（优势比1.53，95%置信区间1.04 - 2.23，P = 0.02），表明低活性等位基因具有部分隐性特征。鉴于5-HTT的功能作用，我们的研究结果表明，5-HTTLPR依赖的功能性5-HTT表达变异是情感障碍的一个潜在遗传易感性因素。如果这一发现得到重复验证，进一步研究5-HTT活性低的基因变体可能有助于情感障碍的鉴别诊断、自杀行为的评估以及对抗抑郁药物良好临床反应的预测。
