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


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=1.14, CI: 1.03–1.26, P=0.015 for the promoter locus (N=3467) and Mantel–Haenszel Weighted odds ratio OR=1.18, CI: 1.05–1.32, P=0.004 for the VNTR locus (N=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.


Affective disorders are among the most common psychiatric disorders worldwide and are listed as one the leading causes of years lived with disabilities.1 Over the last decades, etiological research in affective disorders has focused significantly on the investigation of genetic factors. This is based on considerable evidence suggesting that genes may play a significant role in the predisposition to these disorders.2 Association studies have been advocated as the method of choice to investigate complex traits such as affective disorders.3,4 This, together with the relative simplicity involved in the execution of these studies and the recent exponential grow in the amount of available information on genetic variation, has greatly stimulated the proliferation of association studies in psychiatry, including affective disorders.

The majority of the association studies carried out in affective disorders have focused on genes coding for components of the serotonergic neurotransmission, and more recently, most of the attention has been directed towards variants located in the various genes that code for serotonin receptors and the serotonin transporter. The rational behind the choice of such candidate genes is straightforward, as it is based on a wealth of data suggesting that the serotonin system is involved in the pathophysiology of these disorders (reviewed in Duman5). The rational behind the choice of genetic variants tested is less clear, although as little information is actually available on the potential functional implication of genetic variation on most of the loci tested.

In spite of the large number of association studies investigating genes coding for components of the serotonergic system in affective disorders, it is difficult to draw any consistent conclusion as positive findings tend not to be replicated. Although this inconsistency may be related to methodological differences between studies, population diversity, or a number of possible study errors, a common limitation of individual studies is the lack of sufficient statistical power to detect anticipated small gene effects.3,4 One possible way to circumvent this particular limitation is by means of systematic reviews and meta-analytic tools.6,7 A systematic review is a method to order numerous publications from the literature and to pool data from individual studies when appropriate.8,9 In this study our goal was to retrieve, assess, and combine when applicable, individual studies investigating the association between major depression disorder (MDD) or bipolar disorder (BD) and 5-HT receptors, including the 5-HTT. The accompanying paper10 reviews the studies investigating these genes in suicidal behavior.


Four different database searches were completed, including association studies of MDD and 5-HT receptors, MDD and 5-HTT, BD and 5-HT receptors, and BD and 5-HTT. Given the volume of studies with 5-HTT, a separate search consisting of 5-HTT subheadings was carried out. Initially, our research identified publications through the National Library of Medicine (NLM) MEDLINE and included articles released up to June 2002. The Medical Subject Headings (MeSH) terms used were ‘(serotonin receptor OR serotonergic receptor OR 5-HT1A OR 5-HT1B OR 5-HT1D OR 5-HT1E OR 5-HT1F OR 5-HT2A OR 5-HT2B OR 5-HT2C OR 5-HT3 OR 5-HT4 OR 5-HT5 OR 5-HT6 OR 5-HT7) AND (unipolar disorder OR major depressive disorder OR major depression)’, ‘(serotonin transporter OR serotonergic transporter OR 5-HTT) AND (unipolar disorder OR major depressive disorder OR major depression)’, ‘(serotonin receptor OR serotonergic receptor OR 5-HT1A OR 5-HT1B OR 5-HT1D OR 5-HT1E OR 5-HT1F OR 5-HT2A OR 5-HT2B OR 5-HT2C OR 5-HT3 OR 5-HT4 OR 5-HT5 OR 5-HT6 OR 5-HT7) AND (bipolar disorder OR manic depressive illness)’, ‘(serotonin transporter OR serotonergic transporter OR 5-HTT) AND (bipolar disorder OR manic depressive illness)’ for the four separate searches. Additional articles were found by scanning the list of related articles of the original ones, some review articles and the reference lists. Only articles in English and related to humans were included.

Study selection

The studies included in this systematic review met the following criteria: (a) case–control design, (b) at least one analysis investigating the relation between major depression/unipolar or bipolar disorders and polymorphisms located in genes coding for serotonergic receptors or in the genes coding for serotonergic transporter, (c) diagnosis of major depression/unipolar and bipolar disorders according to a standard diagnostic criteria (DSM, ICD, RDC), (d) inclusion of samples comprising unrelated subjects, (e) thus, family studies were excluded, and finally, (f) being independent from other studies included in this review. In cases of nonindependent studies, only one study was included. In this situation, we gave preference for studies investigating larger samples. Studies that met the inclusion criteria, but did not provide the actual outcome frequencies were not included. Studies in which a control group was absent were not included either. A single reviewer (MA) identified, selected, and assessed the studies to ensure consistency in the selection and processing of the publications. First, the title and abstract were assessed and finally the criteria for inclusion/exclusion were considered.


All polymorphisms of the 5-HT receptors and 5-HTT found in the literature were considered in our review if the inclusion/exclusion criteria were met. In the case of the 5-HT receptors, the great majority of the polymorphisms tested were point mutations (Table 1 and Table 4) and in the case of 5-HTT, two variants have been extensively explored, a 44 base pair (bp) insertion/deletion (ins/del) in the promoter region (Table 2) and a VNTR (various number of tandem repeats) in intron 2 (Table 3). The 44 bp ins/del polymorphism of the 5-HTT results in a short and long variant of the gene. The VNTR polymorphism presents, most commonly, alleles characterized by 9, 10, or 12 repeats.

Table 1 Characteristics of the studies included in this systematic revision that investigated 5-HT receptors in major depression
Table 4 Characteristics of individual studies included in this systematic review that investigated an association between BD and 5-HT receptors
Table 2 Characteristics of the studies included in this systematic review investigating the 5-HTT, 44 bp ins/del promoter polymorphism
Table 3 Characteristics of the studies included in this systematic review investigating the 5-HTT intron 2 VNTR polymorphism

Systematic review and meta-analytic methods

For most polymorphisms, the number of studies retrieved was too small to apply data synthesis/pooling procedures, so, in these cases, only a descriptive analysis is provided. Meta-analyses were performed for the 5-HTT VNTR and promoter variants and the 102 T/C in the 5-HT2A receptor. Homogeneity analysis was performed before pooling the study results to assess if the individual studies could be combined. The Mantel–Haenszel weighted odds ratio (M-HW OR) was used to combine results from different studies.11 We pooled measures of association between allelic variants and the phenotype investigated. We did not combine measures of association with genotypes, as this will imply in excessive subgrouping. With the exception of the VNTR polymorphism, all loci were biallelic and the ORs for each study were calculated always in the same direction. In the case of VNTR, we obtained ORs for each allele while clumping the remaining alleles together. Sensitivity analysis was carried out for overall positive results. This technique ensures for more reliable and consistent finding, avoiding situations in which one single study accounts for the significance of the overall outcome. For all statistical analyses, the Epi6 software was used.


Major depression and 5-HT receptors

Of the 189 articles initially retrieved, 16 articles tested 20 different 5-HT receptor polymorphisms in MDD (Table 1) that were relevant to this review and met the inclusion criteria.12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27 The study by Wu et al28 was excluded because it lacked control cases. The studies by Golimbet et al29 and Serretti et al30,31 were excluded because it was not possible to extract information about allele or genotype frequencies for MDD patients alone, as these studies aimed at investigating the association with personality traits or symptomatology and used samples with different axis I diagnoses. The article by Liu et al32 was not included because the patients had Alzheimer's disease, which was comorbid with depression.

One study investigated 5-HT2A His452Tyr and one study investigated 5-HT6 267 C/T. Two studies investigated the 5-HT1B 861 G/C, 5-HT2C Ser23Cys, 5-HT5A –19 G/C, and 5-HT5A 12 A/T polymorphisms, and three studies investigated the 5-HT2A –1438 A/G polymorphism. Most of these studies did not show evidence of association with MDD (Table 1). Seven studies investigated the 102 T/C variant in the 5-HT2A receptor, prompting us to carry out a meta-analysis of their results. A homogeneity analysis was performed, indicating that the results could be combined (χ2=2.92; df=6, P>0.05). This meta-analysis comprised an overall sample of 768 MDD patients and 959 controls. No evidence was found supporting an association between MDD and this locus (M-HW OR=0.96, CI: 0.84–1.11; Mantel–Haenszel summary (M-HS) χ2=0.28; P=0.597).

Major depression and 5-HTT

The initial search pertaining to 5-HTT and MDD resulted in 72 studies, of which a total of 22 were included in this review (Table 2 and 3). Among these, 11 investigated the promoter 44 bp ins/del polymorphism14,20,33,34,35,36,37,38,39,40,41 and 10 studies investigated the VNTR polymorphism.42,43,44,45 The studies by Kunugi et al46 and by Ogilvie et al47 were excluded since they were not independent from the studies by Kunugi et al36 and Battersby et al,42 both of which were included.

Two separate meta-analyses were carried out with the studies investigating an association between MDD and 5-HTT. One meta-analysis included studies investigating the promoter ins/del locus and the other the VNTR polymorphism. Homogeneity analyses allowed combining results in both cases (promoter ins/del: χ2=3.11; df=10; P>0.05; VNTR: χ2=0.07; df=9, P>0.05). The meta-analysis on studies investigating the promoter 44 bp ins/del polymorphism included 941 MDD patients and 2110 controls. No overall evidence of association was found (M-HW OR=1.08, CI: 0.96–1.22; M-HS χ2=1.65; P=0.198). Similarly, the meta-analysis on the VNTR variant did not provide evidence of association (for allele 9: M-HW OR=1.24, CI: 0.72–2.14; M-HS χ2=0.47; P=0.493; for allele 10: M-HW OR=0.96, CI: 0.84–1.10; M-HS χ2=0.30; P=0.585; for allele 12: M-HW OR=1.03, CI: 0.89–1.18; M-HS χ2=0.10; P=0.747) (Table 3). This analysis included 592 MDD patients and 2094 controls.

BD and 5-HT receptors

The review of association studies between 5-HT receptors and BD initially resulted in 98 studies. From these, 25 publications18,19,22,23,24,25,26,27,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64 were included in our analysis (Table 4). There was one study investigating each of the following loci: 5-HT1A Ile28Val, 5-HT1B Phe124Cys, 5-HT1F-78 C/T, 5-HT1F 528 C/T, 5-HT1F 783 T/A, 5-HT2C GT(12–18)/CT(4–5), 5-HT3A Leu10Leu (C249T), 5-HT3A IVS3 (A+7C), 5-HT3A Leu192Leu (G795A), 5-HT3A Lys277Lys (G1050A), 5-HT3A Arg344His (G1250A), 5-HT3A Leu459Leu (A1596G), 5-HT6 126 G/T, 5-HT6 873 + 30 C/T, 5-HT6 873+128 A/C, 5-HT6 1128 G/C, 5-HT6 1376 T/G, 5-HT7 Lys92Thr and 5-HT7 Leu279Pro. Two studies investigated 5-HT5A 12 A/T polymorphism and three studies investigated each of the following variants: 5-HT2A Thr25Asn, 5-HT2A His452Tyr, 5-HT2A 516 C/T, and 5-HT2C Cys23Ser. Finally, 10 studies investigated the 5-HT2A 102 T/C variant. Most of these studies showed no evidence of positive association with BD. Two studies were the exception if one considers the computed ORs. One of these investigated 5-HT2A58 and the other 5-HT6.63 A meta-analysis was carried out on the 10 studies that investigated the 5-HT2A 102 T/C variant (homogeneity test: χ2=0.38; df=9, P>0.05). The analysis included a total of 1095 BD patients and 1468 controls. No evidence of association was found when results from all studies were combined (M-HW OR=0.98 CI: 0.87–1.10; M-HS χ2=0.13; P=0.722).

BD and 5-HTT

The review of 5-HTT studies in BD initially yielded 63 studies, 23 of which were included. Of these, 11 studied the 44 bp ins/del polymorphism33,34,35,36,37,38,40,41,65,66,67 and 12 studied the VNTR polymorphism.35,36,37,38,40,42,43,44,45,57,66,68 The studies by Mendes de Oliveira et al,69 Kunugi et al,46 and Bellivier et al70 were not included because they were not independent, respectively, from Oliveira et al,41 Kunugi et al36 and Bellivier et al.40 The publication by Ogilvie et al47 was not independent from the study by Battersby et al,42 so we included only the latter. The publications by Serretti et al31 and by Ho et al71 were excluded because the BD patients were part of a larger sample including subjects with other diagnoses and it was not possible to extract data pertaining exclusively to BD patients.

The meta-analysis of studies investigating the 44 bp ins/del polymorphism was carried out including a total of 1382 BD patients and 2085 controls (homogeneity test: χ2=0.98; df=10; P>0.05). The combined results suggested evidence of an association between BD and this locus (M-HW OR=1.14, CI: 1.03–1.26; M-HS χ2=5.95; P=0.015). However, sensitivity analysis suggested that most of the observed overall positive association could be attributed to the effect of one large study (Collier et al34) and to a lesser extent to another one, also relatively large (Rotondo et al65) (Table 5). The 12 repeat allele of the VNTR locus also showed evidence of association with BD, when results from individual studies were combined (Table 3) (M-HW OR=1.18, CI: 1.05–1.32; M-HS χ2= 8.46; P=0.004). This analysis was based on a total of 1368 BD patients and 2252 controls (homogeneity test: χ2=2.14; df=11; P>0.05). However, as observed for the other 5-HTT locus tested, sensitivity analysis indicated that most of the overall positive result could be attributed to the effect of a large study by the same group44 (Table 5).

Table 5 Bipolar disorder, 5-HTT, insertion/deletion polymorphism sensitivity analysis


Over the last years, a large volume of data has been produced exploring the hypothesis that genetic variation at genes coding for serotonergic receptors and/or the serotonin transporter may be involved in the predisposition to affective disorders, and thus account, at least in part, for the strong evidence observed in genetic epidemiological studies supporting the role of genetic factors in affective disorders. 2 The study of these candidate genes is well supported by extensive data from neurochemical, pharmacological, physiological, and animal studies investigating the role of serotonin, its receptors and transporter in the etiology, and treatment of affective disorder.5 In this study, we reviewed a total of 86 association studies that focused on genetic variation located in these candidate genes.

Although a few individual studies reported evidence of association with given serotonin receptor variants, most of the studies were not significant. It is difficult to draw definite conclusions from these studies because most of the individual 5-HT receptor loci have been investigated by only one study. In addition, most of these loci were little polymorphic. This, added to the usually small samples investigated by individual studies, as well as to the unknown functional relevance of the majority of the variants investigated, indicates that most of these studies have important limitations to test the hypothesis that, that particular receptor is involved in the etiology of affective disorders.

Three loci have been explored more consistently throughout the studies. These are 5-HT2A 102 T/C, 5-HTT promoter 44 bp ins/del and 5-HTT intron 2 VNTR. Combining the studies investigating 5-HT2A 102 T/C did not provide any evidence supporting association with either MDD or BD. Although unlikely, this result is not sufficient to refute a possible role of 5-HT2A in affective disorders, as a different variant in this gene could still be implicated. However, this gene is relatively small and studies investigating its genetic variation have suggested strong linkage disequilibrium between different polymorphisms. Thus, if variants other than 5-HT2A 102 T/C were implicated in affective disorders, it is likely that their effect would have been detected in studies investigating 5-HT2A 102 T/C.

Combining results from studies investigating 5-HTT in BD indicated an overall positive effect both for the promoter 44 bp ins/del variant and the intron 2 VNTR. However, in each case, we could not exclude the possibility that this overall result could be attributed to the effect of one particularly large study,34,44 and therefore, it was not possible to draw overall conclusions. Both these studies were among the first ones to investigate the association between 5-HTT and BD. Interestingly, Ioannidis et al72 recently examined the replication validity of association studies and found that, typically, a very strong association is proposed by the first published study reporting the association, and subsequently, there seems to be a tendency for the association to disappear or to become less prominent. In this particular case, however, the two studies in question were considerably larger than all other single studies, and thus, additional, larger studies are especially required before one can properly interpret the 5-HTT pooled results in BD. Recent studies have suggested that the short and long 5HTT promoter alleles may be subdivided into different subtypes according to the particular combination of repeat elements.73 Interestingly, different allelic subtypes have been shown to have different transcriptional activity.74 Therefore, it would be useful if future studies investigating variation at 5-HTT could assess allelic subtypes. Moreover, it would be also important that raw genotypic data be made available on a systematic basis so as to facilitate drawing overall conclusions.

Although meta-analysis is a useful tool to combine results and increase power, meta-analytic studies of genetic associations may also be subject to a number of possible limitations. Among these, the most important, particularly in the context of an overall negative result, is the possibility of true population diversity in the variant associated with the disease. In other words, situations in which, for instance, the 5-HTT 44 ins/del polymorphism would only confer susceptibility for BD in population A and not in population B, or in which the short allele would be implicated in population A and the long allele in population B. If this occurs, not only would meta-analytic studies have limited application, but also positive association studies would tend not to be independently replicated.

In conclusion, we have systematically reviewed association studies in affective disorders investigating candidate genes coding for 5-HT receptors and the 5-HTT. Thus far, there is no conclusive evidence suggesting that variation at genes coding for 5-HT receptors or 5HTT may confer susceptibility for MDD or BD. However, further studies are needed, particularly looking at 5-HTT in BD. It would be interesting if these studies used larger samples and that raw genotypic data were made available, which could increase the power of future meta-analytic studies.


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We thank Alexandra Lalovic, Caroline Kim, Adolfo Sequeira, Iris Groisman, and Firoza Mamdani for their expert academic assistance. This study was partly funded by CIHR Grant MOP-38078 and an AFSP grant.

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Correspondence to G Turecki.

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Anguelova, M., Benkelfat, C. & Turecki, G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 8, 574–591 (2003). https://doi.org/10.1038/sj.mp.4001328

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  • bipolar disorder
  • major depressive disorder
  • genetic association studies
  • genetic polymorphisms
  • serotonin receptors
  • serotonin transporter

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