Leandro Michelon

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 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.

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.

Fatores genéticos e ambientais na manifestação do transtorno bipolar

Bipolar disorder (BD) is a highly prevalent mental disease worldwide. This disorder has a genetic inheritance characterized by complex transmission mechanisms involving multiple genes under the influence of several environmental factors. Many investigation strategies have been put forward in order to identify BD susceptibility genes. Twin, linkage and association studies have contributed to the characterization of its herdability through the identification of genomic regions potentially linked to BD and the candidate genes investigation approach. Because of the complexity of the transmission pattern for BD and its phenotypic heterogeneity many difficulties have emerged in defining exact bipolar susceptibility genes. On the other hand, psychosocial studies point out to relevant environmental factors in the etiology of BD. The increasing understanding of gene expression regulation by epigenetic mechanisms, including gene-environment interaction, and the dimensional approach to the mental disorders offer promissing directions to future researches in order to uncover the factors envolved in the etiology of Bipolar disorder.

Genetics of bipolar disorder

Bipolar disorder (BD) is a worldwide highly prevalent mental disease. This disorder has a genetic inheritance characterized by complex transmission mechanisms involving multiple genes. Many investigation strategies have been put forward in order to identify BD susceptibility genes. Linkage studies reveal markers and candidate genes for the association studies. Monoaminergic system genes and intracellular signaling pathway genes are also important candidates to be investigated in the etiology of this disorder. Recent techniques of gene expression mapping suggest novel genes whose mutations may be responsible for BD. Due to the complexity of the transmission pattern for BD and its phenotypic heterogeneity many difficulties have emerged to exactly define bipolar susceptibility genes. There is currently only preliminary results of genes associated with BD. However, the increasing understanding of gene expression regulation by epigenetic mechanisms and the dimensional approach to mental disorders can give directions for further research in psychiatric genetics.

High Heritability of Telomere Length In Families With Bipolar Disorder

Background Bipolar Disorder (BD) is a highly debilitating mental illness and its etiology and pathophysiology are not completely known yet, despite the evidence of an important genetic component from twin and adoption studies. More recently, BD has been related to a process of accelerated aging, with some studies showing shortened leukocyte telomeres in this population. The purpose of the present study was to investigate genetic and environmental influences on telomere length trait in families with BD, using a variance component approach, by estimating the heritability of this trait as well as co-variate effects. Methods Telomere length (T) was estimated in a sample of 144 individuals, including 60 BD patients from 18 Brazilian families, which was measured in relation to the single copy gene (S) – β-globin gene (HBB) – using a singleplex real time PCR, providing a ratio of number of copies of T by S (T/S). Heritability estimate was obtained by a polygenic mixed model. Results Before adjustment for sex, age and status of disease (null model), the polygenic heritability of telomere length was 0.58. When adjusted for sex, age and status of disease, the heritability continues as 0.58, but when adjusted only for sex and age, it increases to 0.68. Only p value of the effect of age is significant ( Discussion To our knowledge, this is the first study evaluating heritability of telomere length in families with several members affected by bipolar disorder. The heritability estimation for telomere length in those Brazilian families was high (0.68). When calculation for the heritability of this trait was adjusted for the co-variate “status of disease” (bipolar dichotomous co-variate), it decreased a little to 0.58 (as null model). Mapping efforts to identify genetic loci associated with telomere length and other genetic variants on this population are warranted.