NR3C1 and NR3C2 Genes Increase the Risk of Suicide Attempt in Psychiatric Disorder Patients with History of Childhood Trauma.

Background: Hypothalamic-pituitary-adrenal axis gene variants and childhood trauma (CT) are considered risk factors for suicide attempt (SA). The aim of the present study was analyzed gene x environment (GxE) interaction of NR3C1, NR3C2, and CT, and NR3C1 and NR3C2 gene expression in the development of SA with CT. Participants and Methods: A total of 516 psychiatric Mexican patients from Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. Among them, 274 had SA at least once and 242 had not SA. Genetic variants of NR3C1 and NR3C2 were genotyped in all the patients, of which were obtained the CT information from medical records. Additionally, the gene expression of NR3C1 and NR3C2 was also analyzed for a subsample of 96 patients, obtaining the TC information from Childhood Trauma Questionnaire (CTQ). Results: The analysis showed a GxE interaction of NR3C1, NR3C2, and CT (OR=2.8, 95% CI [1.9-3.9], p<0.0001). Interactions were also observed with neglect (OR=2.1, 95% CI [1.4-3.1], p<0.0001), emotional abuse (OR=2.1, 95% CI [1.5-3], p<0.0001), and sexual abuse (OR=2.4, 95% CI [1.4-2.9], p<0.0001) in the prediction of SA. The analysis of gene expression identified an overexpression of NR3C1 in SA patients with high scores for physical and sexual abuse (p<0.0001; p<0.0006, respectively) and emotional neglect (p=0.014). An underexpression was observed of NR3C2, associated with high scores of trauma subtypes (p<0.0001) except physical neglect. Additionally, we observed an overexpression of NR3C1 gene in patients with SA carriers of A allele of rs6191 (p=0.0015). Also, overexpression of NR3C1 gene in carriers of G allele of rs6198 and underexpression of NR3C2 gene in carriers of G allele of rs5522 (p<0.0001). Conclusion: Our findings suggest that genetic variants of NR3C1 and NR3C2 differentially affect expression levels, increasing the susceptibility to SA in psychiatric patients with a history of CT.

Genetic analysis of the ZNF804A gene in Mexican patients with schizophrenia, schizoaffective disorder and bipolar disorder.

BACKGROUND: Evidence suggests that schizophrenia (SCZ), schizoaffective disorder (SAD) and bipolar disorder (BPD) share genetic risk variants. ZNF804A gene has been associated with these disorders in different populations. GWAS and candidate gene studies have reported association between the rs1344706 A allele with SCZ, SAD and BPD in European and Asian populations. In Mexican patients, no studies have specifically analyzed ZNF804A gene variants with these disorders. The aim of the study was to analyze the rs1344706 and identify common and rare variants in a targeted region of the ZNF804A gene in Mexican patients with SCZ, BPD and SAD compared with a control group. METHODS: We genotyped the rs1344706 in 228 Mexican patients diagnosed with SCZ, SAD and BPD, and 295 controls. Also, an additional sample of 167 patients with these disorders and 170 controls was analyzed to identify rare and common variants using the Sanger-sequence analysis of a targeted region of ZNF804A gene. RESULTS: Association analysis of rs1344706 observed a higher frequency of A allele in the patients compared with the control group; however, did not show statistical differences after Bonferronís correction (χ2 = 5.3, p = 0.0208). In the sequence analysis, we did not identify rare variants; however, we identified three common variants: rs3046266, rs1366842 and rs12477430. A comparison of the three identified variants between patients and controls did not show statistical differences (p > 0.0125). Finally, haplotype analysis did not show statistical differences between SCZ, SAD and BPD and controls. CONCLUSIONS: Our findings did not support the evidence suggesting that ZNF804A gene participates in the etiology of SCZ, SAD and BPD. Future studies are needed in a larger sample size to identify the effect of this gene in psychiatric disorders.

Association study of Catechol-O-Methyltransferase (COMT) rs4680 Val158Met gene polymorphism and suicide attempt in Mexican adolescents with major depressive disorder.

AIM: We analyzed the association between SLC6A4, DRD2, COMT and MAOA genes and suicide attempt (SA) in Mexican adolescent patients with major depressive disorder (MDD). METHODS: The sample included 197 adolescents (127 females and 70 males) with principal diagnosis of MDD. Among them, 63 patients had SA at least once and 134 had not SA. The mean age of patients with and without SA was 15 ± 1.4 and 14 ± 1.5 years, respectively. We analyzed the genotype and allele distribution between patients with and without SA of SLC6A4 (5HTTLPR/rs25531), DRD2 (rs6275), COMT (rs4680), and MAOA (uVNTR). RESULTS: We did not find genotype or allele association between SA and SLC6A4 (χ2=0.67, p = 0.71; χ2=0.07, p = 0.77, respectively), DRD2 (χ2=0.05, p = 0.97; χ2=0.003, p = 0.95), and MAOA (females: χ2=0.86, p = 0.64; χ2=0, p = 1/males: χ2=0.008, p = 0.92) genes. However, there were differences in genotype frequencies of COMT/rs4680 between patients with SA and without SA (χ2=11.17, p = 0.003). Also, we observed a high frequency of Met158 allele showing an increased risk of having presented at least one SA (χ2=10.6, p = 0.001; OR = 1.43; 95% CI, 1.17-1.74). CONCLUSIONS: Our findings showed an association between low activity genotype and allele of Val158Met polymorphism of COMT gene and SA in Mexican adolescents with MDD.

Cannabis Use in People With Obsessive-Compulsive Symptomatology: Results From a Mexican Epidemiological Sample.

Recent studies suggest that the endocannabinoid system could play an important role in the physiopathology of obsessive-compulsive disorder (OCD). There are reports of effective treatment with derivatives of tetrahydrocannabinol (THC). The study of the genetic factor associated with psychiatric disorders has made possible an exploration of its contribution to the pharmacological response. However, very little is known about the genetic factor or the prevalence of cannabis use in the Mexican population with OCD. The objective of this study is to compare the prevalence of use and dependence on cannabis in individuals with obsessive-compulsive symptomatology (OCS) with that of individuals with other psychiatric symptoms (psychosis, depression, and anxiety), and to explore the association between genetic risk and use. The study includes a total of 13,130 individuals evaluated in the second stage of the 2016 National Survey of Drug, Alcohol, and Tobacco Use (Encodat 2016), with genetic analysis (polygenic risk scoring) of a subsample of 3,521 individuals. Obsessive symptomatology had a prevalence of 7.2% and compulsive symptomatology a prevalence of 8.6%. The proportion of individuals with OCS who had ever used cannabis was 23.4%, and of those with cannabis dependency was 2.7%, the latter figure higher than that in individuals with other psychiatric symptoms (hypomania, 2.6%; anxiety, 2.8%; depression, 2.3%), except psychosis (5.9%). Individuals with OCS who reported using cannabis had an increased genetic risk for cannabis dependence but not for OCD. We thus cannot know how the increased genetic risk of cannabis dependence in people with OCD is influenced by their pharmacological response to derivatives of THC. The results, however, suggest paths for future studies.

Association between 5-HTTLPR polymorphism, suicide attempt and comorbidity in Mexican adolescents with major depressive disorder.

INTRODUCTION: The World Health Organization reports that suicide is among the leading causes of death for young people. Depression is the most frequently related disorder with suicidal behaviors. There is increasing evidence that suicidal behavior has a strong genetic contribution. Several studies report an association between the genotype "SS" and the "S" allele of the 5-HTTLPR polymorphism of the serotonin transporter gene and suicidal behavior. The aim of the study was to determine the association of variants of the serotonin transporter gene with suicidal attempt and comorbidity in depressed adolescents. METHODS: The frequencies of ss genotypes and s allele were compared between a sample of 200 adolescents with a diagnosis of depression and the antecedent of a suicide attempt who were evaluated with K-SADS-PL and a group of 235 healthy controls. Genotyping of the 5-HTTLPR polymorphism was performed by PCR. RESULTS: Analysis of the frequencies of genotypes and alleles showed a statistically significant difference between the groups (Genotypes: x2=11.1, df=2, p=0.004, Alleles: x2=11.9, df=1, p=0.0009). There were no associations with comorbid disorders. CONCLUSIONS: The results support the hypothesis that the serotonin transporter gene, specifically the s allele and the ss genotype of the 5-HTTLPR polymorphism, are related to the history of depression and suicide attempt in adolescents.

Association study between COMT, DRD2, and DRD3 gene variants and antipsychotic treatment response in Mexican patients with schizophrenia.

PURPOSE: The efficacy of schizophrenia treatments using antipsychotics (APs) has long been established, but the benefit obtained by several patients using conventional APs (typical or atypical) has not been enough. Currently, the genetic study of the primary mechanisms of action of the APs has been focused on the dopaminergic pathways. The objective of this study was to determine if the response phenotypes (responder, resistance to treatment, and ultra-resistance to treatment groups) are associated with six single-nucleotide polymorphisms: COMT (Val158Met), DRD2 (A-241G, C376G, C939T, Taq1A), and DRD3 (Ser9Gly). PATIENTS AND METHODS: We classified the patients through a retrospective/prospective methodology to define response phenotypes. RESULTS: COMT/Val158Met and DRD3/Ser9Gly were associated with the responder group (P<0.05). The single-nucleotide polymorphism A-241G of DRD2 gene was related with the resistant-to-treatment group (P<0.001). Finally, Met/Met of COMT and Ser/Gly of DRD3 genes showed a predictive effect associated with the resistant-to-treatment phenotype. CONCLUSION: Further analyses should be performed to validate these genetic markers as mediators for the response to APs.

El polimorfismo 5-HTTLPR y el intento suicida en adolescentes deprimidos / 5-HTTLPR polymorphism and suicidal attempt in depressed adolescents

La Organización Mundial de la Salud reporta que el suicidio es la tercera causa de muerte más frecuente para jóvenes de 15 a 24 años de edad y la sexta causa de muerte para niños de cinco a 14 años de edad. Los trastornos del estado de ánimo, particularmente la depresión, son los responsables de la mayor parte de los suicidios consumados. Este mayor riesgo de suicidio se ha encontrado en adultos y adolescentes. Existe cada vez mayor evidencia respecto de la hipótesis de que la conducta suicida tiene una fuerte contribución genética. Varios estudios han reportado una asociación positiva entre el genotipo "SS" y el alelo "S" del polimorfismo 5-HTTLPR del gen del transportador de serotonina y la conducta suicida. Objetivo El objetivo del presente trabajo fue establecer la asociación de las variantes polimórficas del gen del transportador de serotonina en pacientes adolescentes deprimidos con y sin antecedente de intento suicida y determinar si la presencia del genotipo "SS" estaba asociada a características específicas de la depresión. Método La muestra estuvo conformada por 53 adolescentes con diagnóstico de depresión. El diagnóstico se realizó con la entrevista diagnóstica semi-estructurada K-SADS-PL. Para la extracción del ADN genómico se obtuvo una muestra de sangre de cada uno de los pacientes. Resultados El análisis genético de las frecuencias de genotipos y alelos no mostró diferencias estadísticamente significativas entre los grupos. Sin embargo, aquellos pacientes con el genotipo "SS" tenían mayor frecuencia de desesperanza. En los pacientes con este genotipo también se encontró mayor número de intentos suicidas. Conclusiones No se observaron diferencias en la frecuencia de alelos entre pacientes con y sin intento suicida; sin embargo, el genotipo "SS" se asoció a algunas características de la depresión.

Suicide is a common cause of death in adolescents, being mainly associated with depression. In addition, the "SS" genotype and the "S" allele of 5-HTTLPR polymorphism of SLC6A4 gene of serotonin transporter have been associated with suicidal behavior. The aims of the present study were to compare the frequency of the polymorphism of SLC6A4 gene in depressed adolescents with and without history of suicidal attempt and to determine if the "SS" genotype was associated with specific clinical features. Method The study examined 53 adolescents who were evaluated with the Diagnostic Interview Schedule for Affective Disorders and Schizophrenia for school-aged children-present and lifetime version (K-SADS-PL). A DNA sample was obtained and 5HTTLPR polymorphisms of SLC6A4 gene were analyzed. Results There were no differences in the frequency of genotype and allele frequencies between groups. However, patients with the "SS" genotype reported a higher frequency of hopelessness and a greater number of suicide attempts. Conclusions The frequency of "SS" genotype did not differ between patients with and without suicidal behavior, but patients with this genotype exhibited differences in clinical features of depression which need further study.