Serotonin transporter gene polymorphism and affective disorder

Kunugi, Hiroshi; Tatsumi, Masahiko; Sakai, Tetsuo; Hattori, Masamichi; Nanko, Shinichiro; Stöber, Gerald; Heils, Armin; Lesch, Klaus‐Peter

doi:10.1016/s0140-6736(96)90993-9

Cited by 89 publications

(40 citation statements)

References 2 publications

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“…Four of these 24 papers contained the same data. 39,44,62,67 Two were about mental disorders other than BPD. 13,71 Three were not association studies.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2005

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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 metaanalytical 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 ¼ 0.41 for the 5-HTTLPR and P ¼ 0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P ¼ 0.35 for the 5-HTTLPR and P ¼ 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. Keywords: bipolar disorder; serotonin transporter; polymorphisms; genetics; association study; meta-analysis Bipolar disorder (BPD), also known as manic-depressive illness, is a frequent and severe psychiatric disorder with the lifetime prevalence between 1 and 2% in the general population, being equally distributed across sexes. 1 The etiology is unknown although the presence of a complex dysfunction at multiple levels such as neurotransmitter system, prefrontallimbic-subcortical circuit and neuroendocrinological system has been suggested. 2 Family studies have indicated a marked increase in lifetime risk of the illness in first-degree relatives of the proband, varying between five and 10 times that of the general population. 3 Twin studies have shown an increased risk in monozygotic co-twins compared with dizygotic co-twins of a proband with BPD. The risk in monozygotic co-twins has been estimated at 45-75 times that of the general population. 3,4 Adoption studies have also shown that the risk of BPD is greater in biological relatives than in adoptive relatives of the probands. 5 Most of the segregation studies have shown that the inheritance of BPD cannot be explained b...

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“…Four of these 24 papers contained the same data. 39,44,62,67 Two were about mental disorders other than BPD. 13,71 Three were not association studies.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2005

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“…Among these, 11 investigated the promoter 44 bp ins/del polymorphism 14,20,[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 al 46 and by Ogilvie et al 47 were excluded since they were not independent from the studies by Kunugi et al 36 and Battersby et al, 42 both of which were included.…”

Section: Major Depression and 5-httmentioning

confidence: 99%

“…Of these, 11 studied the 44 bp ins/del polymorphism [33][34][35][36][37][38]40,41,[65][66][67] and 12 studied the VNTR polymorphism. 35-38,40,42-45, 57,66,68 The studies by Mendes de Oliveira et al, 69 Kunugi et al, 46 and Bellivier et al 70 were not included because they were not independent, respectively, from Oliveira et al, 41 Kunugi et al 36 and Bellivier et al 40 The publication by Ogilvie et al 47 was not independent from the study by Battersby et al, 42 so we included only the latter. The publications by Serretti et al 31 and by Ho et al 71 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.…”

Section: Bd and 5-httmentioning

confidence: 99%

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

2003

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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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“…4 However, the analysis of the association between the 5-HTTLPR polymorphism and susceptibility for several psychiatric diseases (including mood disorders, autism, panic disorder, schizophrenia, Alzheimer's disease, obsessive compulsive disorder, personality traits and depressive symptomatology in mood disorders) in different populations has shown some positive but contradictory findings. [4][5][6][7][8][9][10][11][12][13][14][15] Our own study in the Brazilian population 16 as well as all previous single center analyses in Europe did not reveal any significant association between the serotonin transporter polymorphism and affective disorders or schizophrenia. 5,12,13,17 However, when samples from three different European centers were analyzed together, Collier et al 5 found that the frequency of the low-activity short variant (s) of the 5-HTTLPR was higher among patients with affective disorders than in normal controls.…”

Section: Analysis Of the Serotonin Transporter Polymorphism (5-httlprmentioning

confidence: 77%

Analysis of the serotonin transporter polymorphism (5-HTTLPR) in Brazilian patients affected by dysthymia, major depression and bipolar disorder

et al. 2000

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Serotonin transporter gene polymorphism and affective disorder

Cited by 89 publications

References 2 publications

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

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

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

Analysis of the serotonin transporter polymorphism (5-HTTLPR) in Brazilian patients affected by dysthymia, major depression and bipolar disorder

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