An interaction between the norepinephrine transporter and monoamine oxidase A polymorphisms, and novelty-seeking personality traits in Korean females

The personality traits associated with the noradrenergic system have not yet been clearly established. In the present study, we investigated the variable number of tandem repeats (VNTR) polymorphism of the norepinephrine transporter (NET) and monoamine oxidase A (MAOA), which are major components of the adrenergic system, to elucidate their relationship with personality. A total of 245 normal female Koreans (age 23.05+/-3.07 years, mean+/-SD) volunteered to take part in this study. They filled out a Korean version of the Temperament and Character Inventory (TCI) and were genotyped for the NET and MAOA-VNTR; the NET T-182C and MAOA-uVNTR polymorphisms were checked. We found significant main effect of NET genotype on novelty seeking (NS) score (F=5.43, p=0.021) and significant interaction between the NET and MAOA-uVNTR polymorphisms on NS score (F=11.06, p=0.001). However, there were no relationship between MAOA-uVNTR polymorphisms and NS score, and no association with other temperamental dimensions and these two polymorphisms. Our findings suggest that this functional polymorphism in the noradrenergic gene is associated with novelty seeking in Korean females.     

An interaction between the serotonin transporter promoter region and dopamine transporter polymorphisms contributes to harm avoidance and reward dependence traits in normal healthy subjects

Summary. There is evidence for an association between polymorphisms of serotonin- and dopamine-related genes and temperamental personality traits. Recent findings have shown that interactions between allelic variants of the different genes may contribute to personality traits. We examined the effects of serotonin transporter-linked promoter region (5-HTTLPR) and dopamine transporter (DAT1) gene polymorphisms for associations with the Temperament and Character Inventory (TCI) temperament subscales in 209 Koreans. We found that the variants of 5-HTTLPR interacted with the DAT1 gene polymorphism to influence the HA and RD temperament subscales of TCI. Neither of these two genes affected any subscales of TCI alone. Controlling for the effects of gender and age, we found significant interactions between 5-HTTLPR and DAT1 genes on Harm Avoidance (HA) and Reward Dependence (RD) as measured by the TCI (Hotelling’s Trace = 3.0, P = 0.02). In the presence of the DAT1 10/10 genotype, subjects of group L of 5-HTTLPR had a significantly higher HA score and significantly lower RD score than those of group S (F = 5.04, df = 1, p = 0.03 and F = 8.35, df = 1, p = 0.004, respectively). These findings suggest that the variants of 5-HTTLPR interacted with the DAT1 gene polymorphism to influence the HA and RD temperament subscales of TCI.     

Interaction between serotonin 5-HT2A receptor gene and dopamine transporter (DAT1) gene polymorphisms influences personality trait of persistence in Austrian Caucasians

We examined 89 normal volunteers using Cloninger's Temperament and Character Inventory (TCI). Genotyping the 102T/C polymorphism of the serotonin 5HT2A receptor gene and the ser9gly polymorphism in exon 1 of the dopamine D3 receptor (DRD3) gene was performed using PCR-RFLP, whereas the dopamine transporter (DAT1) gene variable number of tandem repeats (VNTR) polymorphism was investigated using PCR amplification followed by electrophoresis in an 8% acrylamide gel with a set of size markers. We found a nominally significant association between gender and harm avoidance (P=0.017; women showing higher scores). There was no association of either DAT1, DRD3 or 5HT2A alleles or genotypes with any dimension of the TCI applying Kruskal–Wallis rank-sum tests. Comparing homozygote and heterozygote DAT1 genotypes, we found higher novelty seeking scores in homozygotes (P=0.054). We further found a nominally significant interaction between DAT1 and 5HT2A homo-/heterozygous gene variants (P=0.0071; DAT1 and 5HT2A genotypes P value of 0.05), performing multivariate analysis of variance (MANOVA). Examining the temperamental TCI subscales, this interaction was associated with persistence (genotypes: P=0.004; homo-/heterozygous gene variants: P=0.0004). We conclude that an interaction between DAT1 and 5HT2A genes might influence the temperamental personality trait persistence.     

Performance on the Wisconsin Card Sorting Test in schizophrenia and genes of dopaminergic inactivation (COMT, DAT, NET)

The aim of the study was to test an association between polymorphisms of genes connected with dopaminergic inactivation in prefrontal cortex [catechol-O-methyltransferase (COMT), dopamine transporter (DAT), norepinephrine transporter (NET)], and performance on the Wisconsin Card Sorting Test (WCST), in schizophrenic patients. The number of perseverative errors (WCST-P), non-perseverative errors (WCST-NP), completed corrected categories (WCST-CC), conceptual level responses (WCST-%CONC) and set to the first category (WCST-1st CAT) were measured. Genotyping was done for the Val108(158)Met polymorphism of the COMT gene (79 patients), the 3'UTR VNTR polymorphism of the DAT gene (124 patients) and the 1287 A/G polymorphism of the NET gene (63 patients). Male schizophrenic patients with Val/Val genotype of COMT obtained better results on WCST-P, while female patients had worse results on the WCST-NP compared with the remaining genotypes. There was a slight trend for patients with the A9/A9 genotype of DAT and with the A/A genotype of NET to perform better on some domains of the WCST, compared with other genotypes. A limitation to the interpretation of results could be small number of patients studied as well as variable psychopathological state and medication during cognitive testing.     

Serotonin transporter gene polymorphism and personality traits in primary alcohol dependence.

We tested the hypothesis of an association between the serotonin transporter (5-HTT) gene regulatory region polymorphism and the Temperament and Character Inventory (TCI) personality dimension of Harm Avoidance. For the study, 124 subjects seeking inpatient treatment for primary alcohol dependence were grouped by their 5-HTT genotype and assessed with the TCI. Genotypes differed statistically significantly in Harm Avoidance but not in any other personality trait. This gives support to the hypothesis that the TCI temperament Harm Avoidance is associated with serotonergic neurotransmission in primary alcohol dependence.     

Serotonin transporter gene polymorphism and schizoid personality traits in the patients with psychosis and psychiatrically well subjects.

BACKGROUND AND OBJECTIVES: serotonin transporter (5-HTT) gene allelic variants were shown to be associated with Neuroticism and Harm Avoidance but the results were not replicated in other studies. The current investigation was undertaken in a further attempt to study the relationship between 5-HTT polymorphism and personality traits. SUBJECTS AND METHODS: to evaluate a spectrum of personality traits, MMPI was administered to a sample including patients with affective disorders (n=114), patients with schizophrenia spectrum illnesses (n=110) and psychiatrically well controls (n=124). All groups were genotyped for VNTR-17 and functional insertion-deletion (5-HTTLPR) polymorphisms. RESULTS: an association was found between 5-HTTLPR polymorphism and scores on three MMPI scales: Psychopathic deviance, Paranoia and Schizophrenia in patients with affective disorders and S chizophrenia in normal subjects. Both affected and control individuals with 'ss' genotype exhibited lower scores on these scales. CONCLUSION: we demonstrated that functional deletion/insertion allelic variation associated with decreased expression of serotonin transporter ('s' allele or 'ss' genotype) may restrict expression of schizoid traits in normal subjects and patients with affective disorders.     

Polymorphisms in the serotonin transporter gene and their relationship to two temperamental traits measured by the formal characteristics of behavior-temperament inventory: activity and emotional reactivity

Results obtained in earlier studies indicate that 5-HTT gene polymorphisms may have a certain impact on individual differences with respect to temperamental traits. The aim of our study was to determine whether the occurrence of various alleles of the serotonin transporter gene is related to the variability of two temperamental traits postulated in the Regulative Theory of Temperament (RTT)--activity and emotional reactivity. We have demonstrated that the 5-HTTLPR polymorphism is associated with one of the RTT temperamental traits--activity. Neither the relationship between the regulatory region polymorphism and emotional reactivity nor the association between the intron 2 VNTR polymorphism and the temperamental traits under study has been confirmed.     

Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis

Recent findings demonstrated the role of neurotransmitters in the aetiopathogenesis of sudden unexpected deaths in infancy. Although genes involved in serotonin metabolism have been proposed as risk factors for sudden infant death syndrome (SIDS), the contribution of additional neurotransmitters and genes different from the serotonin transporter (SLC6A4, 5-HTT) has not been investigated. Considering the common metabolic pathway and synergism between dopamine and serotonin, the role of dopamine transporter (SLC6A3, DAT) and monoamine oxidase A (MAOA) genes in SIDS and stillbirth (sudden intrauterine unexplained death, SIUD) was investigated. Genotypes and allelic frequencies of DAT and MAOA were determined in 20 SIDS and five stillbirth cases and compared with 150 controls. No association was found between DAT polymorphisms and SIDS either at genotype (P = 0.64) or allelic (P = 0.86) level; however, a highly significant association was found between MAOA genotypes (P = 0.047) and alleles (P = 0.002) regulating different expression patterns (3R/3R vs 3.5R/3.5R + 4R/4R) in SIDS + SIUD and controls. Analysis of combined 5-HTTLPR (serotonin transporter linked polymorphic region)/MAOA genotypes revealed that frequency of L/L-4R/4R genotype combination was eightfold higher in SIDS + SIUD than in controls (P < 0.001). Findings are discussed considering the metabolic association among DAT, 5-HTT and MAOA with special emphasis on the linked action of 5-HTT/MAOA in regulating serotonin metabolism of SIDS and SIUD infants.     

Low novelty seeking and high self directedness scores in alcohol-dependent patients without comorbid psychiatric disorders homozygous for the A10 allele of the dopamine transporter gene

The gene for the human dopamine transporter DAT1 displays several polymorphisms, including a 40-bp variable number of tandem repeats (VNTR) ranging from 3 to 13 copies in the 3′-untranslated region (UTR) of the gene. Some hints for an association of certain VNTR with psychiatric disorders, behavioural problems and temperament traits have been found. This study explored possible associations between the most frequent DAT1 polymorphism, namely the A10 VNTR, and personality traits as measured by the Temperament and Character Inventory (TCI) and the NEO Five Factor Inventory (NEO-FFI) in alcohol-dependent patients (ADP). One hundred and forty-four ADP and 144 age-, educational level- and sex-matched controls (CO) were genotyped and interviewed with the TCI and NEO-FFI. ADP showed higher neuroticism, lower extraversion, lower openness, lower agreeableness and lower conscientiousness than CO on the NEO-FFI and higher scores in harm avoidance, reward dependence and self transcendence and lower scores in self directedness and cooperativeness on the TCI than controls. There were no genetic links regarding those personality traits, the diagnosis of alcohol dependence and the VNTR. Only in a subgroup of ADP, those without psychiatric co-diagnoses and homozygous for A10, significantly lower scores in novelty seeking and higher scores in self directedness than in all the other ADP and CO could be detected. Summarizing, the 40-bp VNTR did not help to differentiate between ADP and CO, but might contribute to some personality dimensions in certain ADP subgroups.     

Prediction of antidepressant response to milnacipran by norepinephrine transporter gene polymorphisms

OBJECTIVE: With a multitude of antidepressants available, predictors of response to different classes of antidepressants are of considerable interest. The purpose of the present study was to determine whether norepinephrine transporter gene (NET) and serotonin transporter gene (5-HTT) polymorphisms are associated with the antidepressant response to milnacipran, a dual serotonin/norepinephrine reuptake inhibitor. METHOD: Ninety-six Japanese patients with major depressive disorder were treated with milnacipran, 50-100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery-Asberg Depression Rating Scale. Assessments were carried out at baseline and at 1, 2, 4, and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants. RESULTS: Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response, whereas the A/A genotype of the NET G1287A polymorphism was associated with a slower onset of therapeutic response. In contrast, no influence of 5-HTT polymorphisms on the antidepressant response to milnacipran was detected. CONCLUSIONS: The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran.     

Serotonin Transporter Gene Polymorphism and Schizoid Personality Traits in Patients with Psychosis and Psychiatrically Well Subjects

Background and Objectives: Serotonin transporter (5-HTT) gene allelic variants were shown to be associated with Neuroticism and Harm Avoidance but the results were not replicated in other studies. The current investigation was undertaken in a further attempt to study the relationship between 5-HTT polymorphism and personality traits.

Subjects and Methods: To evaluate a spectrum of personality traits, MMPI was administered to a sample including patients with affective disorders (n=114), patients with schizophrenia spectrum illnesses (n=110) and psychiatrically well controls (n=124). All groups were genotyped for VNTR-17 and functional insertion-deletion (5-HTTLPR) polymorphisms.

Results: An association was found between 5-HTTLPR polymorphism and scores on three MMPI scales: Psychopathic deviance, Paranoia and Schizophrenia in patients with affective disorders and Schizophrenia in normal subjects. Both affected and control individuals with ‘ss’ genotype exhibited lower scores on these scales.

Conclusion: We demonstrated that functional deletion/insertion allelic variation associated with decreased expression of serotonin transporter (‘s’ allele or ‘ss’ genotype) may restrict expression of schizoid traits in normal subjects and patients with affective disorders.     

Genetics of the serotonergic system in suicidal behavior

Genetic factors contribute to the risk of psychopathology in many psychiatric conditions, but the specific genes are yet to be identified. Neurotransmitter alterations are implicated in the etiology of psychopathology based, in part, on studies of neurotransmitter receptors and their biosynthetic or degradative enzymes in postmortem tissue. Identification of the altered receptors and enzymes serves to identify candidate genes of potential etiological significance. Polymorphisms in these genes can contribute to alterations in protein function in vivo that are part of the neurochemical underpinnings of psychopathologies such as major depressive disorder, psychoses, alcoholism, personality disorders, aggressive-impulsive traits, or suicidal behavior. Altered serotonergic function is implicated in the etiology and pathogenesis of several major psychiatric conditions. In particular, there is much evidence for an association of lower serotonergic function and suicidal behavior. Thus genes related to the serotonergic system are candidate genes worthy of study as part of the genetic diathesis for suicidal behavior. This review examines the following polymorphisms in the serotonin biosynthetic enzyme tryptophan hydroxylase (TPH; A779C substitution), the serotonin transporter (5-HTT, 5-HTTLPR allele), the 5-HT(1B) receptor (G861C, C129T substitution) and the 5-HT(2A) receptor (T102C) for their relationship to suicidal behavior. For the TPH gene, we found the less common U or A allele variant of the A779C polymorphism was associated with suicide attempt. Other studies have found the U allele to be associated with aggression and lower serotonergic function in vivo. A 44 base pair insertion/deletion in the 5' flanking promoter region of the 5-HTT gene may result in less 5-HTT expression and 5-HTT binding. We examined 220 cases postmortem and found no association between the promoter genotype and 5-HTT binding. We also found no association with major depressive disorder (MDD), suicide or pathological aggression, despite finding significantly fewer 5-HTT sites in the prefrontal cortex of depressed and/or suicide cases. In genomic DNA samples from 178 unrelated subjects, we detected two polymorphisms for the 5-HT(1B) receptor at nucleotides 861 and 129. However, no association between either polymorphism and depression, suicide, aggression, or alcoholism was observed. There are two common polymorphisms for the 5-HT(2A) receptor gene in humans. The results of studies of 5-HT(2A) receptor gene polymorphisms do not indicate significant major associations with suicidal behavior. In contrast, the 5-HT(2A) receptor itself is reported to be increased in suicide. Functional polymorphisms involving the promoter region that affect gene expression may explain this finding. Studies of candidate genes related to serotonergic function in brain are increasingly used to establish genetic alterations contributing to psychiatric illness. The most meaningful studies combine the study of candidate genes with direct measures of related proteins as well as psychopathology.     

The 5-HT2A -1438 A/G and 5-HTTLPR polymorphisms and personality dimensions in adolescent anorexia nervosa: association study

Disturbances of serotonergic neurotransmission and temperamental vulnerability have both been implicated in the pathogenesis of anorexia nervosa (AN). We genotyped the -1438 A/G polymorphism in the 5-HT2A receptor gene and serotonin transporter linked-polymorphic region (5-HTTLPR) in 132 adolescent subjects with AN and in 93 healthy controls. Personality dimensions in AN patients were assessed with the Temperament and Character Inventory. In a case-control model, we tested the hypothesis that these genetic variants confer susceptibility to AN. We also analyzed whether two polymorphisms show association with temperamental and character traits. No significant difference was found in the 5-HTTLPR frequency between AN patients and controls; however, there was a statistical trend towards a higher frequency of the A allele of the -1438 A/G polymorphism in patients than in controls (64.9 vs. 56.7%, chi2 test, p=0.08). We also found a significant association between the A allele of this polymorphism and two temperamental traits. Patients homozygous for the A allele showed lower reward dependence than G/G homozygotes, and A/A homozygotes showed lower harm avoidance than heterozygotes. Low reward dependence and harm avoidance were more characteristic of the restrictive-type AN than of other subtypes of the disorder. No association of 5-HTTLPR with personality dimensions in AN patients was observed. Our results may suggest that the A allele of the -1438 A/G polymorphism confers some genetic risk for adolescent AN patients, especially in those with personality traits, which are typical of the restrictive-type AN.     

Association study of the dopamine and serotonin transporter genetic polymorphisms and methamphetamine abuse in Chinese males

Summary. The dopamine transporter (DAT) and the serotonin transporter (5-HTT) play important roles in methamphetamine (METH) dependence because they are the target of METH action. For this study, the association between the DAT and 5-HTT polymorphisms and METH dependence were investigated for a Chinese-male sample population. The investigated polymorphisms included those of the DAT 3′-variable number tandem repeat, the 5-HTT gene promoter and a 5-HTT variable number tandem repeat polymorphisms. No significant difference was demonstrated for genotype or allele frequency, when comparing METH dependent and control cases for the DAT and the 5-HTT polymorphisms. The findings of this study suggest that these polymorphisms do not play major roles in METH dependence in the Chinese-male population. Received January 8, 2002; accepted October 2, 2002 Published online December 9, 2002 RID="*" ID="*"  The experiments in this study were performed in the Molecular Genetics Laboratory, Department of Psychiatry, Veterans General Hospital-Taipei, Taiwan, ROC Acknowledgements This work was supported by Grant DOH89-TD-1095, provided by the Department of Health, Taiwan, ROC, and Grant VGH89-398-15, provided by the Veterans General Hospital-Taipei. The authors wish to thank Mr. C.-T. Feng, T.-H. Liu and the staff at the Taiwan Taipei Detention Center for their assistance with sample collection, and Ms S.-C. Chiang for her assistance in statistical analysis. Authors' address: Dr. C.-J. Hong, Department of Psychiatry, Veterans General Hospital-Taipei, No. 201 Shih-Pai Road, Sec. 2, 11217, Taipei, Taiwan, Republic of China, e-mail: cjhong@vghtpe.gov.tw     

Analysis of Association between Norepinephrine Transporter Gene Polymorphisms and Personality Traits of NEO-FFI in a Japanese Population

Objective

Norepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger''s theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger''s personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model.

Methods

After written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students.

Results

A significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms.

Conclusion

We conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence-related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires.     

Association studies of candidate genes in bipolar disorders

The aim of the investigation was to test genes for predisposition to bipolar affective disorder. Therefore, we studied candidate genes in a sample of unrelated patients (n = 102) and healthy controls (n = 79) of Austrian origin, searching for a possible association between polymorphic DNA markers of 5 candidate genes (serotonin transporter, 5-HTT; serotonin 2a receptor, 5-HT2a; dopamine D2 receptor, DRD2; dopamine D3 receptor, DRD3; dopamine transporter, DAT1) and bipolar disorder. There was an association between allelic and genotypic frequencies of 5-HTT and affection status (p = 0.014 and p = 0.017, respectively). However, after correction for multiple comparisons (Bonferroni), these results did not remain significant. Nevertheless, the findings might suggest that alterations in the structure of 5-HTT are involved in the pathogenesis of bipolar disorder, which could have major implications in treatment. No association between 5-HT2a, DRD2, DRD3, DAT1 and bipolar disorder was found.     

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder.

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.     

Association between Novelty Seeking and the -521 C/T polymorphism in the promoter region of the DRD4 gene

Association between the human personality trait 'Novelty Seeking' and the polymorphism of the DRD4 gene was first reported by Ebstein and Benjamin in 1996. This was soon followed by replication studies in various ethnic groups and by studying the role of other neurotransmitter receptor and transporter genes in the genetic determination of human temperament. More recently, several polymorphic sites of the upstream regulatory region of the DRD4 gene have been described. Among these the -521 C/T single nucleotide polymorphism (SNP) was shown to be associated with the Novelty Seeking (NS) scores of the Temperament and Character Inventory (TCI) in a Japanese male population. We have investigated the -521 C/T SNP polymorphism in a Caucasian (Hungarian) population, and here we report a replication of the Japanese findings, in an association study involving 109 healthy Hungarian volunteers. We found a weak association between NS and CC vs CT or TT genotypes (P < 0.06). Examination of this relation in male and female sex groups, however, strengthened the association for females (P < 0.01), but showed no genotypic effect for males.     

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.