Alejandro Aguilar

A family-based association study of the 5-HT-1Dβ receptor gene in obsessive-compulsive disorder

Abstract Pharmacological studies have shown that sumatriptan, a selective ligand of the serotonin 5-HT-1Dbeta autoreceptor, modifies obsessive-compulsive disorder (OCD) symptoms. The current study analysed the G861C polymorphism of the 5-HT-1Dbeta gene in a sample of 72 trios. Genotyping data were analysed using the Family-Based Association Test (FBAT). We did not replicate the previously reported linkage disequilibrium between the G861 variant and OCD. However, a quantitative trait analysis, assessing severity of OCD symptoms and defined as YBOCS score, confirmed the finding that subjects with a preferential transmission of the G861 variant showed higher YBOCS Obsession scores compared to patients carrying the C861 allele. These preliminary findings may indicate that the 5-HT-1Dbeta receptor gene could be involved in the severity of obsession symptoms in OCD. However, it is important to perform the replication of these findings in larger sample sizes of informative families.

Association study of MAO-A and DRD4 genes in schizophrenic patients with aggressive behavior.

Genes involved in dopamine neurotransmission are interesting candidates to be analyzed in schizophrenia and aggressive behavior. Therefore, we analyzed the functional polymorphisms of the dopamine receptor D4 (DRD4) and monoamine oxidase A (MAO-A) genes in a sample of 71 schizophrenic patients assessed with the Overt Aggression Scale to measure aggressive behavior. CLUMP analysis of the DRD4 48-bp repeat-exon III polymorphism in schizophrenic patients showed significant differences between the aggressive behavior and the nonaggressive groups (T1 = 18.77, d.f. = 6, p = 0.0046; T3 = 6.54, p = 0.0195). However, analysis of the promoter polymorphism of the MAO-A gene revealed no significant association between aggressive and nonaggressive patients. Finally, analysis of Overt Aggression Scale dimensions exhibited significant differences for the DRD4 and MAO-A genes. Our preliminary findings suggest that the DRD4 and MAO-A genes may be involved in aggressive schizophrenic patients.

Family-Based Association Study between the Monoamine Oxidase A Gene and Obesity: Implications for Psychopharmacogenetic Studies

Family studies have reported that obesity has a strong heritable component. It has been suggested that a neurotransmitter dysfunction could be involved in mental disorders and obesity; therefore, candidate genes in psychiatric disorders could be a risk factor for obesity. We investigated the association between the monoamine oxidase A (MAO-A) gene and obesity. Fifty obese subjects and their parents were included in the study. Two polymorphisms designated EcoRV and upstream variable number tandem repeats of the MAO-A gene were analysed using polymerase chain reaction. For analysis of the families, the transmission disequilibrium test (TDT) was applied. The TDT analysis of the EcoRV polymorphism showed in obese subjects with a body mass index (BMI) ≧35 kg/m2 a preferential transmission of the low activity-related allele (χ2TDT = 8.0, p = 0.005). Our findings may provide evidence of a candidate gene involved in obese subjects with a BMI ≧35 kg/m2.

Monoamine Oxidase A and B Gene Polymorphisms and Negative and Positive Symptoms in Schizophrenia

Given that schizophrenia is a heterogeneous disorder, the analysis of clinical characteristics could help to identify homogeneous phenotypes that may be of relevance in genetic studies. Linkage and association studies have suggested that a locus predisposing to schizophrenia may reside within Xp11. We analyzed uVNTR and rs1137070, polymorphisms from MAOA and rs1799836 of MAOB genes to perform single SNP case-control association study in a sample of 344 schizophrenia patients and 124 control subjects. Single polymorphism analysis of uVNTR, rs1137070 and rs1799836 SNPs did not show statistical differences between cases and controls. Multivariate ANOVA analysis of clinical characteristics showed statistical differences between MAOB/rs1799836 and affective flattening scores (F = 4.852, P = 0.009), and significant association between MAOA/uVNTR and affective flattening in female schizophrenia patients (F = 4.236, P = 0.016) after Bonferronis correction. Our preliminary findings could suggest that severity of affective flattening may be associated by modifier variants of MAOA and MAOB genes in female Mexican patients with schizophrenia. However, further large-scale studies using quantitative symptom-based phenotypes and several candidate variants should be analyzed to obtain a final conclusion.

Association study between the MDR1 gene and clinical characteristics in schizophrenia

OBJECTIVE Schizophrenia is a complex psychiatric disorder, characterized by disturbed patterns of thought and affecting 0.3-2.0% of the world population. Previously, the multidrug resistance 1 (MDR1) gene has been associated with schizophrenia in treatment response studies in psychotic patients. The aim of this study was to determine the association between MDR1 gene polymorphisms and clinical characteristics in patients with schizophrenia. METHODS Positive and negative symptoms of schizophrenia were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in 158 Mexican patients with schizophrenia. Analyses of MDR1 gene polymorphisms were performed using TaqMan technology. A multivariate ANOVA was performed with MDR1 polymorphisms and gender as independent variables. RESULTS Males with the G/G genotype of MDR1 rs2032582 presented significantly higher levels of delusions (p = 0.02). When comparing female vs. male groups, the difference was statistically significant (p = 0.0003). Analyses of the MDR1 gene rs1045642 variant showed no significant differences. CONCLUSION Our findings suggest that male carriers of the G allele of variant rs2032582 exhibit greater severity of delusions; however, these results should be taken as preliminary, and replication studies in other populations of different ethnic origins are required to confirm these findings.

Association study of DRD3 gene in schizophrenia in Mexican sib-pairs

Schizophrenia is a heritable, complex mental disorder. We analysed the DRD3 gene as a candidate to be related to schizophrenia and clinical features in affected sib-pairs. A positive association with the -250A/Ser9 haplotype and a trend toward an association with formal thought disorder were observed. A synergic effect of DRD3 polymorphisms on schizophrenia susceptibility is suggested.

A family-based association study of the HTR1B gene in eating disorders

Objective: To explore the association of three polymorphisms of the serotonin receptor 1Dβ gene (HTR1B) in the etiology of eating disorders and their relationship with clinical characteristics. Methods: We analyzed the G861C, A-161T, and A1180G polymorphisms of the HTR1B gene through a family-based association test (FBAT) in 245 nuclear families. The sample was stratified into anorexia nervosa (AN) spectrum and bulimia nervosa (BN) spectrum. In addition, we performed a quantitative FBAT analysis of anxiety severity, depression severity, and Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS) in the AN and BN-spectrum groups. Results: FBAT analysis of the A-161T polymorphism found preferential transmission of allele A-161 in the overall sample. This association was stronger when the sample was stratified by spectrums, showing transmission disequilibrium between the A-161 allele and BN spectrum (z = 2.871, p = 0.004). Quantitative trait analysis showed an association between severity of anxiety symptoms and the C861 allele in AN-spectrum participants (z = 2.871, p = 0.004). We found no associations on analysis of depression severity or preoccupation and ritual scores in AN or BN-spectrum participants. Conclusions: Our preliminary findings suggest a role of the HTR1B gene in susceptibility to development of BN subtypes. Furthermore, this gene might have an impact on the severity of anxiety in AN-spectrum patients.

Pharmacogenetic Study of Antipsychotic Response To Treatment In Mexican Patients with Schizophrenia: Analysis of Response And Resistance

Background The efficacy of antipsychotics treatment in schizophrenia patients has long been established; however, clinical response to these drugs is not the same in all patients. Genetic variability has been proposed as the main reason for the different outcomes.The dopaminergic pathways, the principal mechanism of action of the antipsychotics, have been the main focus of pharmacogenetic studies in schizophrenia. Some functional single nucleotide polymorphisms (SNPs) have been associated with dopamine disposition or dopamine receptor expression, modifying the response to treatment. The aim of the study was to analyze the association between two response phenotypes (patients with response and resistant) and COMT (Val58Met), DRD2 (A-241G, C/G exon 8, C939T, Taq1A) and DRD3 (Ser9Gly) gene polymorphisms. Methods Treatment response was retrospectively/prospectively assessed. First, we gathered all reliable antipsychotics assays from medical files and through interviews with attending physicians. If these data were not conclusive, a mandatory follow-up period was added with regularly scheduled ratings (using the Positive and Negative Symptom Scale PANSS and the Functional Assessment Scale for Comprehensive Treatment of Schizophrenia FACT-Sz).Treatment response was defined on a ≥ 30% decrease on the total PANSS score (with an antipsychotic different from clozapine). The sample was classified in two main phenotypes: 95 patients on response to treatment group and 81 on resistant-to-treatment group. The genotyping of the COMT (Val58Met), DRD2 (A-241G, C/G exon 8, C939T, Taq1A), and DRD3 (Ser9Gly) gene polymorphisms was performed with allelic discrimination, using TaqMan assays. Differences in genotypes and allele frequencies between the phenotypes of patients were calculated using the X2 test. Also, we performed a logistic regression analysis to predict the likelihood of the resistance-to-treatment phenotype. Results Analysis of Val158Met/COMT showed differences between the response and the resistance groups. The GG genotype (Val/Val) was more frequent in the response group than the resistance group (47% vs. 33%, X2=6.26, 2 df , p=0.04) . We also found allele differences between groups (X2=6.65, 1 df, p Discussion The COMT/Val158Met SNP (Val/Val) was associated with the response to treatment phenotype. This finding is consistent with the antipsychotics proposed mechanism of action. The antipsychotic efficay on lowering the hyperdopaminergic state would be greater in those patients with the high-activity COMT genotype. The DRD2 SNPs analysis, the main target of several studies, did not show any significant association with the phenotypes. The COMT and DRD3 gene analyses could be associated with the resistant-to-treatment patients, so they elicit the possibility as plausible mediators of the resistance to treatment for schizophrenia.One of the limitations of this study is the size of the sample. Further analyses should be performed for the validation of these SNPs as mediators for the response or resistance to antipsychotics.