The different serotonin (5-HT) receptors, including the serotonin transporter (5-HTT), are excellent candidate genes for suicide and suicidal behavior, and thus, they have been investigated in a large number of allelic association studies. The individual results of these studies have been inconsistent and definite conclusions are difficult to establish. A reliable method for assessing individual studies and generating combined results is provided by systematic reviews using meta-analytical techniques. In this study, we carried out a systematic review of studies investigating 5-HT receptors and the 5-HTT in suicidal behavior. Studies were identified by means of MEDLINE database searches and by scanning reference lists. More than 190 articles were reviewed and 26 met the inclusion criteria. In all, 14 studies investigated six different 5-HT receptor loci and 12 studies investigated the 5-HTT promoter 44 bp insertion/ deletion polymorphism. Two specific meta-analyses were carried out, pooling studies investigating the 5-HT2A 102 T/C and the 5-HTT promoter loci that included, respectively, a total of 1599 and 2539 subjects. The combined evidence was significant for association with the 5-HTT locus (Mantel-Haenszel weighted odds ratio (M-H w OR) ¼ 1.17 CI : 1.04-1.32, P ¼ 0.009), but not for the 5-HT2A 102 T/C variant (M-H w OR) ¼ 1.09 CI : 0.93-1.27, P ¼ 0.319). The 5-HTT result was robust and remained significant following sensitivity analysis, suggesting that 5-HTT may play a role in the predisposition to suicide.
The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR ¼ 1.14, CI: 1.03-1.26, P ¼ 0.015 for the promoter locus (N ¼ 3467) and Mantel-Haenszel Weighted odds ratio OR ¼ 1.18, CI: 1.05-1.32, P ¼ 0.004 for the VNTR locus (N ¼ 3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between BD and 5-HTT.
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