A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders

Abstract

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.

Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

“…39,41,42,58 Clinical association studies have further examined the relationship between SERTLPR alleles and psychiatric disorders and anxiety-related personality traits, [59][60][61][62][63][64][65][66] suicide, 67,68 alcoholism, 69,70 response to antidepressants [71][72][73] and brain function as revealed by MRI scans. [74][75][76][77] Although many studies have reported correlations between SERTLPR alleles and SERT expression levels or clinical phenotype, almost an equal number of studies have not.…”

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

“…During our reiterative review process, two meta-analyses of the studies on 5-HTTLPR and intron 2 VNTR were published. 18,19 Anguelova et al's 18 review, which did not include family-based studies, showed small and significant ORs for both polymorphisms. On the other hand, in Lotrich and Pollock's review, 19 which conducted separate analyses for population-based and familybased studies, the results did not reach statistical significance.…”

“…The search strategy contained 'bipolar disorder', 'genetics' and 'serotonin' as keywords: 'bipolar disorder' and ('genetics' or 'serotonin'). The bibliographies of the initially selected papers and the five review papers on the genetics of BPD 3,6,8,18,19 were also searched.…”

Serotonin transporter gene (5-HTT) polymorphism and major depressive disorder in patients in Bogotá, Colombia

“…Regarding the controversial results reported in the literature on the association of the 5-HTT gene in/ del polymorphism and major depression, it may be that sample size in some of the non-conclusive studies was very small and, thus, hindered their statistical power for finding significant differences between patients and controls, or they may have been affected by the selection of cases with very heterogeneous psychiatric phenotypes, a lack of adequate classification of cases and controls, the age of the compared groups, or the geographic origin, among other reasons (20,21). With the increased number of studies of this polymorphism and the subsequent increase in sample size, a greater statistical significance has been registered for this association, especially in the meta-analyses that have been undertaken.…”

“…Some authors have found this statistical association between the 5-HTT (in/del O indel) polymorphism and mood disorders, particularly major depression, shown additionally in meta-analyses such as that of López-León (19-21). Anguelova, et al, also found a strong association between the 5HTT gene in/del polymorphism and the risk of suicide (22), and other authors demonstrated the association between this polymorphism and bipolar affective disorder (20,23). However, in Western European descendants, Hoehe, et al, found no significant differences in the genotypic or allele frequencies of the 5-HTT polymorphism in 36 patients with major depression, 79 with bipolar I disorder, and 294 controls (24).…”