Cho H J, Meira-Lima I, Cordeiro Q, Michelon L, Sham P, Vallada H, Collier D A
Institute of Psychiatry, King's College London, London, UK.
Mol Psychiatry. 2005 Aug;10(8):771-81. doi: 10.1038/sj.mp.4001663.
The serotonin transporter (5-HTT) is a candidate gene for bipolar disorder (BPD). It has been investigated for association with the illness in a series of studies, but overall results have been inconsistent and its role in the disorder remains controversial. Systematic reviews using meta-analytical techniques are a useful method for objectively and reproducibly assessing individual studies and generating combined results. We performed two meta-analyses of published studies--both population-based and family-based studies--investigating the association between BPD and the 5-HTT gene-linked polymorphic region (5-HTTLPR) and the intron 2 variable numbers of tandem repeats (VNTR) polymorphisms. The literature was searched using Medline and Embase to identify studies for inclusion. We statistically joined population-based and family-based studies into a single meta-analysis. For both polymorphisms, our review revealed significant pooled odds ratios (ORs): 1.12 (95% CI 1.03-1.21) for the 5-HTTLPR and 1.12 (95% CI 1.02-1.22) for the intron 2 VNTR. Meta-regression showed that neither the study type (population-based vs family-based; P=0.41 for the 5-HTTLPR and P=0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P=0.35 for the 5-HTTLPR and P=0.66 for the intron 2 VNTR) significantly contributed to the heterogeneity of the meta-analyses. The observed ORs could be regarded simply as a very small but detectable effect of the 5-HTT, which has an additive effect when combined with other susceptibility loci. Alternative hypotheses on this finding were also discussed: a stronger effect of the haplotypes involving the two polymorphisms or other SNP markers; a more direct effect of these polymorphisms on specific phenotypes of BPD; and the presence of gene-environment interaction as a mediator of the genetic effects of 5-HTT.
血清素转运体（5-HTT）是双相情感障碍（BPD）的一个候选基因。在一系列研究中，人们对其与该疾病的关联性进行了调查，但总体结果并不一致，其在该疾病中的作用仍存在争议。使用荟萃分析技术进行系统评价是客观且可重复地评估个体研究并得出综合结果的有用方法。我们对已发表研究（包括基于人群的研究和基于家系的研究）进行了两项荟萃分析，以调查BPD与5-HTT基因连锁多态性区域（5-HTTLPR）以及内含子2可变数目串联重复序列（VNTR）多态性之间的关联。通过检索Medline和Embase来查找纳入研究的文献。我们将基于人群的研究和基于家系的研究进行统计学合并，纳入到一项单一的荟萃分析中。对于这两种多态性，我们的综述显示了显著的合并优势比（OR）：5-HTTLPR为1.12（95%置信区间1.03 - 1.21），内含子2 VNTR为1.12（95%置信区间1.02 - 1.22）。荟萃回归分析表明，无论是研究类型（基于人群的研究与基于家系的研究；5-HTTLPR的P = 0.41，内含子2 VNTR的P = 0.91）还是样本种族（白种人与非白种人；5-HTTLPR的P = 0.35，内含子2 VNTR的P = 0.66），均未对荟萃分析的异质性产生显著影响。观察到的OR可简单视为5-HTT的一个非常小但可检测到的效应，当与其他易感基因座结合时具有累加效应。本文还讨论了关于这一发现的其他假设：涉及这两种多态性或其他单核苷酸多态性（SNP）标记的单倍型的更强效应；这些多态性对BPD特定表型的更直接效应；以及基因 - 环境相互作用作为5-HTT遗传效应的介导因素的存在情况。
