Ivanor Meira-Lima

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

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 meta-analytical 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=0.41 for the 5-HTTLPR and P=0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P=0.35 for the 5-HTTLPR and P=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.

Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder

Family and twin studies have supported a strong genetic factor in the etiology of obsessive‐compulsive disorder (OCD), although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. In this cross‐sectional study, we have examined the allelic and genotypic frequencies of a Val‐158‐Met substitution in the COMT gene, a 44‐base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5‐HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects. There were no observed differences in the frequencies of allele and genotype between patients and control groups for the COMT, the 5HTTLPR and the T102C 5HT2A gene polymorphisms. In contrast, a statistically significant difference between OCD patients and controls was observed on the genotypic distribution (χ2 = 16.7, 2df, P = 0.0002) and on the allelic frequencies (χ2 = 15.8, 1df, P = 0.00007) for the C516T 5HT2A gene polymorphism. The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in our sample. However, further studies using larger samples and family based methods are recommended to confirm these findings.

Association study of the INPP1, 5HTT, BDNF, AP-2β and GSK-3β GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder

In the present study we investigated the influence of a series variants in genes (the serotonin transporter, glycogen synthase kinase-3beta, inositol polyphosphatase 1-phosphate, brain-derived neurotrophic factor and activator protein 2beta) related to the action of lithium carbonate, a drug used for prophylaxis in mood disorders. We used a sample of unrelated patients with bipolar disorder type I on lithium therapy for at least 2 years who met the proposed response criteria for prophylactic response. Of the 134 patients, 61 patients were considered full responders, 49 non-responders and 24 partial responders. No significant differences were observed for the genotype or allele frequencies for good, partial and poor responders for the five gene variants: for BDNF G196A (genotype: chi2 = 3.67, 4 d.f., p = 0.45; allele: chi2 = 2.31, 2 d.f., p = 0.31); for INPP1 C973A (genotype: chi2 = 1.35, 4 d.f., p = 0.85; allele: chi2 = 0.04, 2 d.f., p = 0.98); for AP-2beta [CAAA](4/5) (genotype: chi2 = 3.18; 4 d.f., p = 0.52; allele: chi2 = 0.92, 2 d.f., p = 0.063); for 5HTTLPR (genotype: chi2 = 0.67, 4 d.f., p = 0.96; allele: chi2 = 0.27, 2 d.f., p = 0.87); for GSK-3beta A-1727T (genotype: chi2 = 3.55, 4 d.f., p = 0.47; allele: chi2 = 0.48, 2 d.f., p = 0.78). These investigated variants are not predictive factors for lithium prophylactic response in our sample of bipolar disorder type I patients. However, it is still possible that a subgroup of a diverse ethnic ancestry may be predisposing to some of those variants for lithium response.

Analysis of a polymorphism in the promoter region of the tumor necrosis factor alpha gene in schizophrenia and bipolar disorder: further support for an association with schizophrenia

Sir – Activation of the inflammatory response system has been observed in the schizophrenia and affective disorders.1,2 Investigations of the role of the inflammatory response in these psychiatric disorders include analysis of the immune mediators at the gene level, so the genetic polymorphism of specific cytokine loci has been investigated in psychiatric disorders.3,4 Recently, Boin et al5 investigated a biallelic variant (-G308A) of the TNF- gene directly related to increased production of these cytokines, and found a significant association with schizophrenia. Interestingly, the TNF- gene is located in the region 6p21.1–21.3, near the HLA region, where linkage and association studies have suggested a locus of susceptibility to schizophrenia.6

Angiotensinogen and angiotensin converting enzyme gene polymorphisms and the risk of bipolar affective disorder in humans.

A possible participation of the renin-angiotensin system (RAS) components with mood disturbances has been suggested in both animal and pharmacological models. In this cross-sectional study, we examined the association between functional polymorphisms in the angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes in 115 bipolar affective disorder (BPAD) patients and 323healthy control subjects. The ACE I/D variant did not show any difference in allelic frequencies and genotypic distribution between the groups. In contrast, when studying the AGT M235T polymorphism we found that the M allele was more frequently observed in BPAD patients than in controls (chi(2)=6.766, d.f.=1, P=0.009). Using multivariate logistic models the strongest odds ratio resulted from a dominant genetic model (OR=3.0; CI (95%) 1.7-5.3] Our data suggest an association between the AGT M235 genotype and increased susceptibility for BPAD in these Brazilian patients. These findings are consistent with the hypothesis that the RAS system plays a role in regulating the mood

Association study of dopamine D2 and D3 receptor gene polymorphisms with cocaine dependence.

Genetic factors play a role in the vulnerability to cocaine dependence. The reinforcing properties of cocaine are related to the dopaminergic system, and, in particular, the dopamine receptors have been linked to the reward mechanisms. The present study examines the role of the variants TaqI A of the dopamine D2 receptor gene and BalI of the dopamine D3 receptor gene in a Brazilian sample consisting of 730 cocaine dependents and 782 healthy controls. The studied polymorphisms did not show any difference in allelic frequencies or genotypic distribution between the groups. Our data do not support a role for the dopamine D2 receptor gene TaqI A and dopamine D3 receptor gene BalI gene polymorphisms in the susceptibility to cocaine dependence in a Brazilian sample.

Allelic association analysis of phospholipase A2 genes with schizophrenia

Several studies suggest increased activity of phospholipase A2 in schizophrenic patients. In the present study, variants of four genes coding for phospholipase A2 enzyme groups (sPLA2, cPLA2, iPLA2 and PAFAH) were analysed in a case–control sample using 240 schizophrenic patients and 312 healthy controls. No difference was observed on the allelic and genotypic distribution of cPLA2 and sPLA2 gene polymorphisms among the groups. The PAFAH variant was very rare in our population and therefore not informative. A significant allelic (χ2=5.86, P=0.0085, odds ratio=1.38, 95% confidence interval, 1.08–1.77) and genotypic (χ2=5.4, P=0.02) association with the iPLA2 gene polymorphism was found. In conclusion, our data suggested that iPLA2 may play a role as a susceptibility gene for schizophrenia in our sample; however, confirmatory studies in independent samples are needed.

Allelic association analysis of the functional insertion/deletion polymorphism in the promoter region of the serotonin transporter gene in bipolar affective disorder

The human serotonin transporter gene (5-HTT) is a candidate for the pathogenesis of mood disorders, including bipolar disorder (BPD). The 5-HTT gene has a 44-bp insertion/deletion polymorphism within the promoter region (5-HTTLPR) with 2 allelic forms, the long (l) and the short (s) variants, which affect transcriptional rates of the 5-HTT gene. Association between the low-activity s variant and BPD has been suggested but remains controversial, as replication has not been consistent. In the present study, we examined the frequency of this polymorphism in a group of 266 Brazilian BPD patients and 306 control subjects. Genotyping for the 5-HTTLPR was performed using PCR. The allele frequencies were found to differ between BPD patients and controls (p=0.03), with a higher frequency of the l allele in the patients compared with the controls (60.5% vs 54.4%). The distribution of genotypes also differed significantly between cases and controls (x2=10.4, 2 df, p=0.005), with higher frequency of heterozygous l/s genotype in the BPD patient group (52.6% vs 44%). Because prior evidence from gene expression studies indicated that l/s and s/s genotypes are not distinguishable biochemically, we compared the distribution of the l/l genotype and the combined group l/s plus s/s between case and controls, but there was no significant difference (x2=0.22). Likewise, a logistic regression model considering a dominant role for the s variant was not significant (OR=0.92, 95% CI 0.64–1.32). Our results suggest that the low-activity s variant does not influence susceptibility to BPD in our population.

Genes relacionados ao metabolismo dos fosfolípides como fatores de risco para o transtorno afetivo bipolar

The studies of genetic epidemiology provides consistent evidence of genetic factors having a major role on the risk for the bipolar affective disorder, although, vulnerability genes have not yet been identified in unequivocal form. The authors show that phospholipids play an important role in the cellular signalling processes, besides this, some studies with mood-stabilisers neurochemistry suggest that these drugs act in the phospholipase regulated signalling views. They conclude that analysis of gene variants that code enzymes of the phospholipids metabolism as potential susceptibility genes can extend the knowledge concerning the risk factors and the physiopatological mechanisms underling this mood disturbance.