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

Oliveira, João Ricardo Mendes de; Carvalho, Daniel Resende; Pontual, Deyse; Gallindo, Rodrigo Melo; Sougey, Éverton Botelho; Gentil, Valentim; Lafer, Beny; Maia, L G S; Morais, M.; Matioli, Sérgio Russo; Vallada, Homero; Moreno, Ricardo Alberto; Nishimura, Agnes L.; Otto, Paulo Alberto; Passos‐Bueno, Maria Rita; Zatz, Mayana

doi:10.1038/sj.mp.4000725

Cited by 27 publications

(13 citation statements)

References 21 publications

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“…48,59 The 31 papers finally selected reported 43 studies related to the review objective in total since each paper frequently reported several separate studies. In total, 17 population-based studies 9,14,33,34,38,46,50,51,56,60,61,66,[68][69][70] and six family-based studies 12,32,42,53,63,74 were about 5-HTTLPR. A total of 16 population-based studies 27,33,35,38,41,47,[49][50][51]54,56,58,60,61,70,75 and four family-based studies 12,52,57,63 were about the intron 2 VNTR.…”

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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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%

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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“…Genetic variants of the serotonin transporter (5-HTT) have also been associated with psychotic disorders Malhotra et al, 1998;Hranilovic et al, 2000;Kaiser et al, 2001;Tsai et al, 2002]. However, there is also a wealth of publications that fail to support these findings [Gutierrez et al, 1995;Rao et al, 1998;Shinkai et al, 1998;He et al, 1999;Oliveira et al, 2000;Haider and Zahid, 2002;Serretti et al, 2002]. Discordant findings in studies of complex genetic diseases have been attributed to disease heterogeneity although other factors such as sample size, ethnic origin and symptomatology may also influence results.…”

Section: Introductionmentioning

confidence: 99%

Serotonergic polymorphisms and psychotic disorders in populations from North Spain

Mata¹,

Arranz²,

Patiño

et al. 2003

American J of Med Genetics Pt B

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There is strong biological evidence relating alterations in the serotonergic system with mental disorders. These alterations may be originated at the DNA level by sequence mutations that alter the functioning of serotonin receptors and transporter. To test this hypothesis we investigated three genetic variants of the 5-HT2A receptor (-1438G/A, 102T/C and His452Tyr) and two variants of the serotonin transporter (a VNTR in the second intron and a 44 bp insertion/delition in the promoter region of the gene) in a clinical sample recruited in a human isolate and in surrounding areas in Northern Spain (N = 257) and in ethnically matched controls (N = 334). No clear association was found between 5-HT2A variants and psychosis. However, marginal associations were observed between the 5-HTT LPR and VNTR variants and psychosis (P≤0.05) indicating a minor contribution to psychosis of genetic alterations in this gene.

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

Cited by 27 publications

References 21 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

Serotonergic polymorphisms and psychotic disorders in populations from North Spain

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