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Clozapine (CLZ) is an atypical antipsychotic reserved for patients with refractory psychosis, but it is associated with a significant risk of severe adverse reactions (ADRs) that are potentiated with the concomitant use of alcohol. Additionally, pharmacogenetic studies have explored the influence of several genetic variants in CYP450, receptors and transporters involved in the interindividual response to CLZ. Herein, we systematically review the current multiomics knowledge behind the interaction between CLZ and alcohol intake, and how its concomitant use might modulate the pharmacogenetics. CYP1A2*1F, *1C and other alleles not yet discovered could support a precision medicine approach for better therapeutic effects and fewer CLZ ADRs. CLZ monitoring systems should be amended and include alcohol intake to protect patients from severe CLZ ADRs.

Research reported that sucralose induces metabolic derangements via gut microbiota modulation. However, rebaudioside A (reb A) exposure on gut microbiota has barely been evaluated. The aim of this study was to examine the gut microbiota response to sucralose or reb A in rats under two dietary conditions. Male Wistar rats (150–200 g) on normal diet (ND) or high-fat diet (HFD) were randomized to receive sucralose (SCL), reb A (REB), glucose (GLU, control), or sucrose (SUC). After eight weeks, fecal samples were analyzed by 16S ribosomal RNA gene sequencing. The diversity and the structure of the gut microbiota were not modified by NNS. In ND rats, SCL decreased phylum Firmicutes and increased Bacteroidetes and its genus Bacteroidia. At class level, in HFD rats, REB reduced Bacilli proportions. The genus Romboutsia was reduced with SCL and REB along ND. Lactobacillus increased with SCL and reduced with REB in HFD. After comparative analyses between the two types of diets, we observed that only HFD in combination with SCL increased Bacilli and diminished Bacteroidiaabundances relative to ND. Exposure to NNS, at equivalent doses to the ADI, slightly induce modifications on gut microbiota in ND and HFD feeding rats, and the effects were more pronounced with sucralose ingestion combined with the HFD regimen. Further studies are needed to examine the potential mechanisms involved.

Introduction: Posttraumatic stress disorder (PTSD) is a complex multifactorial disorder influenced by the interaction of genetic and environmental factors. Analyses of epigenomic and transcriptomic modifications may help to dissect the biological factors underlying the gene-environment interplay in PTSD. To date, most human PTSD epigenetics studies have used peripheral tissue, and these findings have complex and poorly-understood relationships to brain alterations. Studies examining brain tissue may help characterize the brain-specific transcriptomic and epigenomic profiles of PTSD. In this review, we compiled and integrate brain-specific molecular findings of PTSD from humans and animals. Methods: A systematic literature search according to the PRISMA criteria was performed to identify transcriptomic and epigenomic studies of PTSD, focusing on brain tissue from human postmortem samples or animal-stress paradigms. Results: Gene- and pathway-level convergence analyses revealed PTSD-dysregulated genes and biological pathways across brain regions and species. A total of 243 genes converged across species, 17 of them significantly enriched for PTSD. Chemical-synaptic transmission and signaling by G-protein-coupled receptors (GPCRs) were consistently enriched in across -omics and species. Discussion: Our findings point out dysregulated genes highly replicated across PTSD studies in humans and animal models and suggest a potential role for the corticotropin-releasing hormone/orexin pathway in PTSD’s pathophysiology. Further, we highlight current knowledge gaps and limitations and recommend future directions to address them.

Resumen Antecedentes La aceleracion del reloj epigenetico se ha asociado con una reduccion en la esperanza de vida. Los individuos con diagnostico de algun trastorno psiquiatrico presentan una reduccion en la esperanza de vida, y algunos estudios la han correlacionado con un envejecimiento acelerado. Objetivo El presente estudio tiene el objetivo de explorar si la presencia de algun trastorno psiquiatrico podria acelerar el reloj epigenetico en gemelos monocigoticos. Metodos Se incluyeron un total de 15 pares de gemelos monocigoticos. La edad epigenetica en celulas de sangre periferica fue estimada mediante algoritmos publicados previamente, utilizando el microarreglo 450 K Beadchip. Resultados Encontramos que en los gemelos con diagnostico de algun trastorno psiquiatrico podria aumentar el reloj epigenetico en comparacion con su gemelo sin trastorno psiquiatrico. Discusion y conclusion La presencia de algun trastorno psiquiatrico podria acelerar el reloj epigenetico en gemelos homocigoticos, pero se requieren estudios con muestras de mayor tamano para aclarar esta relacion.

espanolIntroduccion. Se han identificado algunos factores de riesgo para el trastorno del espectro autista (TEA) como es el caso de la edad parental avanzada. La edad parental avanzada es un factor de riesgo que ha sido muy explorado en poblaciones escandinavas; sin embargo, no existen reportes en ninos de ascendencia mexicana. Objetivo. El presente trabajo tiene el objetivo de analizar si la edad parental avanzada es un factor de riesgo para TEA en una muestra de ninos mexicanos. Metodo. Un total de 1 068 ninos de la Ciudad de Mexico se incluyeron en un estudio de casos-controles, de los cuales 162 contaban con diagnostico de TEA. Regresiones logisticas multivariable, ajustadas por confusores, se realizaron para explorar el efecto de la edad parental avanzada en el riesgo para TEA. Resultados. La edad paterna avanzada en ninos mexicanos aumento el riesgo para TEA; tambien, una diferencia de edad de 10 anos entre los padres presenta un mayor riesgo. Discusion y conclusion. El efecto de la edad paterna avanzada en los ninos mexicanos fue mucho mas bajo que aquella reportada para otras poblaciones. La edad paterna avanzada y la diferencia entre la edad parental puede ser un factor de riesgo para TEA en poblacion mexicana. Sin embargo, se requieren analisis en poblaciones con mayor tamano de muestra EnglishIntroduction. Risk factors for autism spectrum disorders (ASD) have been identified, as is the case of advanced parental age. Advanced parental age as an ASD risk factor has been studied in Scandinavian populations; there are no reports for Mexican children. Objective. The present work aim is to analyze if advanced parental age is a risk factor for ASD in a Mexican children sample. Method. Mexican children (N = 1 068) participated in a case-control study, 162 had an ASD diagnosis. Multivariate logistic regression adjusted by cofounders was performed to explore the effect of paternal age on ASD risk. Results. Advanced paternal age in Mexican children increases the risk for ASD, and also, a difference of 10 years between parental ages have a higher risk. Discussion and conclusion. The effect of advanced paternal age in Mexican children was lower than those reported previously for other populations. Advanced paternal age and difference between parental ages could be a risk factor for ASD in Mexican population. Nevertheless, the analysis of larger sample sizes is required.

Suicidal behavior is result of the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide). Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. We identified 153 differentially methylated sites between individuals with low and high-PRS. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment (CHD7, RFX4, KCNA1, PLCB1, PITX1, NUMBL) and ATP binding (KIF7, NUBP2, KIF6, ATP8B1, ATP11A, CLCN7, MYLK, MAP2K5). Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

Objective: Individuals with schizophrenia and substance use disorders have a poor prognosis and increased psychiatric symptoms. The present study aimed to explore the association of 106 genes in individuals with schizophrenia and comorbid substance use through a next-generation sequencing (NGS) analysis and different in silico algorithms. Methods: We included 105 individuals diagnosed with schizophrenia and a family history of schizophrenia, of whom 49 (46.67%) presented comorbid substance use. Using NGS, we sequenced 106 genes previously associated with schizophrenia. Logistic regression models were used to assess differences in allele frequencies, and a generalized gene-set analysis was performed at the gene level. Functional annotations were performed using different algorithms and databases. Results: We identified a total of 3,109 variants, of which 25 were associated with schizophrenia and comorbid substance use and were located in regulatory and coding regions. We found low-frequency variants in COMT p.Ala72Ser, independently of p.Val158Met, that were associated with substance use. The endocannabinoid functional variant FAAH p.Pro129Thr was also associated with substance use. Conclusions: Genetic variants of genes related to dopaminergic and cannabinoid neurotransmitter systems were associated with comorbid substance use in schizophrenia. Nevertheless, more studies with larger sample sizes are needed to confirm our findings.

Risperidone has been significant correlated with a direct effect of interleukin-6 (IL-6) levels in patients with schizophrenia. This fact allows the opportunity to link the probable immunomodulatory effect of antipsychotic medication. Specially, a proper functioning of IL-6 pathway plays a potential role in the treatment or development of schizophrenia. Our primary aim was to perform a systematic review and meta-analysis to determine the effect of risperidone on IL-6 levels in individuals with schizophrenia. Studies were identified through a systematic search using PubMed, Scopus, and Web of Science databases. The articles found were subjected to the inclusion and exclusion criteria; then, the mean and standardised differences were extracted to calculate the standardised mean differences using the CMA software. IL-6 levels in individuals with schizophrenia were compared before and after receiving risperidone as treatment. Increased levels of IL-6 levels were observed in individuals with schizophrenia who received risperidone (point estimate 0.249, lower limit 0.042, upper limit 0.455, p-value 0.018). In the Asian population sub-analysis, no statistically significant differences were observed (point estimate 0.103, lower limit −0.187, upper limit 0.215, p value 0.890). When we compared individuals with schizophrenia to the control groups, a significant increase of IL-6 levels was observed in the group with schizophrenia (point estimate 0.248, lower limit 0.024, upper limit 0.472, p-value 0.30). Risperidone appears to play an important role in IL-6 levels in schizophrenia. Potential implications of increased IL-6 levels in people with schizophrenia should be considered in future studies.KEY POINTSIncreased levels of IL-6 levels were observed in individuals with schizophrenia who received risperidone.Risperidone appears to play an important role in IL-6 levels in schizophrenia.This study could serve for future research focussed on IL-6. Increased levels of IL-6 levels were observed in individuals with schizophrenia who received risperidone. Risperidone appears to play an important role in IL-6 levels in schizophrenia. This study could serve for future research focussed on IL-6.

Alterations in eating behavior characterized eating disorders (ED). The genetic factors shared between ED diagnoses have been underexplored. The present study performed a genome-wide association study in individuals with disordered eating behaviors in the Mexican population, blood methylation quantitative trait loci (blood-meQTL), summary data-based Mendelian randomization (SMR) analysis, and in silico function prediction by different algorithms. The analysis included a total of 1803 individuals. We performed a genome-wide association study and blood-meQTL analysis by logistic and linear regression. In addition, we analyzed in silico functional variant prediction, phenome-wide, and multi-tissue expression quantitative trait loci. The genome-wide association study identified 44 single-nucleotide polymorphisms (SNP) associated at a nominal value and seven blood-meQTL at a genome-wide threshold. The SNPs show enrichment in genome-wide associations of the metabolic and immunologic domains. In the in silico analysis, the SNP rs10419198 (p-value = 4.85 × 10−5) located on an enhancer mark could change the expression of PRR12 in blood, adipocytes, and brain areas that regulate food intake. Additionally, we found an association of DNA methylation levels of SETBP1 (p-value = 6.76 × 10−4) and SEMG1 (p-value = 5.73 × 10−4) by SMR analysis. The present study supports the previous associations of genetic variation in the metabolic domain with ED.

There is little recent information about the prevalence of symptomatology of mental health disorders in representative population samples in Mexico. To determine the prevalence of mental health symptoms in Mexico and its comorbidity with tobacco, alcohol, and drug use disorder (SUD), we used the 2016–17 National Survey of Drug, Alcohol, and Tobacco Use (Encuesta Nacional de Consumo de Drogas, Alcohol y Tabaco, ENCODAT 2016–2017). The data were collected from households using a cross-sectional, stratified, multistage design, with a confidence level of 90% and a response rate of 73.6%. The final sample included 56,877 completed interviews of individuals aged 12–65, with a subsample of 13,130 who answered the section on mental health. Symptoms of mania and hypomania (7.9%), depression (6.4%), and post-traumatic stress (5.7%) were the three main problems reported. Of this subsample, 56.7% reported using a legal or illegal drug without SUD, 5.4% reported SUD at one time on alcohol, 0.8% on tobacco, and 1.3% on medical or illegal drugs, 15.9% reported symptoms related to mental health, and 2.9% comorbidity. The prevalence found is consistent with those reported in previous studies, except for an increase in post-traumatic stress, which is consistent with the country’s increase in trauma.

Eating disorders are psychiatric disorders characterized by disturbed eating behaviors. They have a complex etiology in which genetic and environmental factors interact. Analyzing gene-environment interactions could help us to identify the mechanisms involved in the etiology of such conditions. For example, comethylation module analysis could detect the small effects of epigenetic interactions, reflecting the influence of environmental factors. We used MethylationEPIC and Psycharray microarrays to determine DNA methylation levels and genotype from 63 teenagers with eating disorders. We identified 11 comethylation modules in WGCNA (Weighted Gene Correlation Network Analysis) and correlated them with single nucleotide polymorphisms (SNP) and clinical features in our subjects. Two comethylation modules correlated with clinical features (BMI and height) in our sample and with SNPs associated with these phenotypes. One of these comethylation modules (yellow) correlated with BMI and rs10494217 polymorphism (associated with waist-hip ratio). Another module (black) was correlated with height, rs9349206, rs11761528, and rs17726787 SNPs, these polymorphisms were associated with height in previous GWAS. Our data suggest that genetic variations could alter epigenetics, and that these perturbations could be reflected as variations in clinical features.

Genetic factors have been implicated in suicidal behavior. It has been suggested that one of the roles of genetic factors in suicide could be represented by the effect of genetic variants on gene expression regulation. Alteration in the expression of genes participating in multiple biological systems in the suicidal brain has been demonstrated, so it is imperative to identify genetic variants that could influence gene expression or its regulatory mechanisms. In this study, we integrated DNA methylation, gene expression, and genotype data from the prefrontal cortex of suicides to identify genetic variants that could be factors in the regulation of gene expression, generally called quantitative trait locus (xQTLs). We identify 6,224 methylation quantitative trait loci and 2,239 expression quantitative trait loci (eQTLs) in the prefrontal cortex of suicide completers. The xQTLs identified influence the expression of genes involved in neurodevelopment and cell organization. Two of the eQTLs identified (rs8065311 and rs1019238) were previously associated with cannabis dependence, highlighting a candidate genetic variant for the increased suicide risk in subjects with substance use disorders. Our findings suggest that genetic variants may regulate gene expression in the prefrontal cortex of suicides through the modulation of promoter and enhancer activity, and to a lesser extent, binding transcription factors.

Background Circulating cell-free mitochondrial DNA (cf-mtDNA) fragments in blood plasma have been reported in patients with schizophrenia (SZ). Although the relationship of cf-mtDNA to the cognitive status of patients with SZ has not yet been explored, it is known that cognitive impairment in SZ compromises the functional and social capacity of these patients and diminishes their quality of life. In this sense, the assessment of the severity of cognitive impairment in a Mexican population with SZ and its association with cf-mtDNA levels in blood plasma may provide the possibility of using cf-mtDNA as a biomarker to determine the status of the disease and the possible ensuing changes over time. Methods Subjects for a case-control study will be recruited. cf-mtDNA obtained from blood plasma will be quantified by real-time polymerase chain reaction, using melting curve technology with SYBR green as amplification marker. Patients with SZ will be grouped into those with severe, mild, and no cognitive impairment according to Montreal Cognitive Assessment scale scores, to determine differences between cognitive performance and cf-mtDNA levels in blood plasma. Ethics and communication This study has been approved by the ethics and investigation committees of the High Specialty Regional Hospital of Mental Health (Hospital Regional de Alta Especialidad de Salud Mental); project No. HRAESM/DG/RP/1128/2018. We plan to communicate our research findings in scientific conferences and in peer-reviewed journals. Conclusion It is known that cognitive dysfunction provokes negative effects in an SZ patient´s life. This project aims to provide better knowledge about the role of cf-mtDNA in the pathogenesis of cognitive impairment in SZ, as an attempt to achieve improvements to the existing treatments, thereby helping to prevent major cognitive deterioration.

Adverse conditions in early life, including environmental, biological and social influences, are risk factors for ill-health during aging and the onset of age-related disorders. In this context, the recent field of social epigenetics offers a valuable method for establishing the relationships among them However, current clinical studies on environmental changes and lifespan disorders are limited. In this sense, the Tlaltizapan (Mexico) cohort, who 52 years ago was exposed to infant malnutrition, low income and poor hygiene conditions, represents a vital source for exploring such factors. Therefore, in the present study, 52 years later, we aimed to explore differences in clinical/biochemical/anthropometric and epigenetic (DNA methylation) variables between individuals from such a cohort, in comparison with an urban-raised sample. Interestingly, only cholesterol levels showed significant differences between the cohorts. On the other hand, individuals from the Tlaltizapan cohort with more years of schooling had a lower epigenetic age in the Horvath (p-value = 0.0225) and PhenoAge (p-value = 0.0353) clocks, compared to those with lower-level schooling. Our analysis indicates 12 differentially methylated sites associated with the PI3-Akt signaling pathway and galactose metabolism in individuals with different durations of schooling. In conclusion, our results suggest that longer durations of schooling could promote DNA methylation changes that may reduce epigenetic age, nevertheless, further studies are needed.

The aim of this study was to explore the knowledge, emotions and perceived stressors by healthcare workers who were in contact with infected patients during the COVID-19 outbreak. An online cross-sectional survey was applied. Data were collected from N = 263 healthcare workers in Tabasco State, Mexico. We developed and administered a questionnaire, which consisted of sociodemographic characteristics, plus four sections. The sections evaluated were (1) knowledge of COVID-19, (2) feelings/emotions during the COVID-19 outbreak, (3) factors that caused stress and (4) factors that helped to reduce stress. Surveyed individuals were divided into three groups: physicians, nurses and other healthcare workers. When we evaluated their knowledge of COVID-19 we observed that the majority of healthcare workers in the three groups reported that they knew about COVID-19. Physicians indicated that they felt insecure about practicing their profession (62.5%) due to the high risk of being in contact with SARS-CoV-2. With regards to stressor factors, the risk of transmitting COVID-19 to their families was the main factor causing moderate to high stress (95.4%). Finally, we found that “your profession puts your life at risk” was the only factor associated with feeling nervous and scared (PR: 3.15, 95% CI: 1.54–6.43). We recommended health education campaigns, introductory courses on COVID-19 and other infectious diseases, management protocols and the provision of protection equipment to health workers in order to reduce personal and professional fears of contagion and to improve the health system in Mexico when facing epidemics.

The prevalence of comorbid psychiatric disorders among patients with eating disorders (ED) is higher than the general population. Individuals diagnosed with eating disorders have changes in their body mass index which could promote severe metabolic disruptions. This study aimed (1) to report the prevalence of comorbid psychiatric disorders among a Mexican adolescent sample diagnosed with eating disorders, (2) to compare our results with the prevalence of psychiatric disorders reported from a national survey of mental health of adolescents, (3) to compare the presence of psychiatric comorbidities between ED diagnoses, and (4) to explore the relationship of these comorbidities with the body mass index. In the study, we included 187 Mexican adolescents diagnosed with eating disorders. The psychiatric comorbidities were evaluated using the Mini International Neuropsychiatric Interview for children/adolescents, and a revised questionnaire on eating and weight patterns. We found that 89% of the Mexican adolescents diagnosed with ED had another psychiatric comorbidity. Major depressive disorder (52.40%) and suicide risk (40%) were the most prevalent comorbidities. Attention and deficit hyperactivity disorder (ADHD) prevalence was different between ED diagnosis, and adolescents with binge-eating disorder and ADHD had the higher body mass index. Our results showed that in this sample of Mexican adolescents, the presence of comorbidities could impact body mass index. This emphasizes the importance that clinicians take into consideration the presence of psychiatric comorbidities to achieve an integrative treatment for adolescents diagnosed with ED.

The acceleration of the epigenetic clock has been associated with a reduction in life expectancy. Individuals diagnosed with a psychiatric disorder have a reduction in life expectancy, and some studies have correlated it with accelerated aging.The present study aims to explore whether the presence of any psychiatric disorder could accelerate the epigenetic clock in monozygotic twins.A total of 15 pairs of monozygotic twins were included. Epigenetic age in peripheral blood cells was estimated by previously published algorithms, using the 450K Beadchip microarray.We found that in twins with a diagnosis of a psychiatric disorder, the epigenetic clock could increase compared to their twin without a psychiatric disorder.The presence of some psychiatric disorder could accelerate the epigenetic clock in homozygous twins, but studies with larger samples are required to clarify this relationship.

Clinical evidence suggests that inflammation is a key factor to understand the causes of depressive symptoms. Fluoxetine is one of the main first-line medications used for depression, and it is hypothesized that it participates in the decrease of pro-inflammatory cytokines. Hence, our aim was to perform a meta-analysis and systematic review to understand the interaction of fluoxetine in the IL-1β, IL-6 and TNF-α inflammatory process. Studies identified in PubMed and Scopus databases were used to perform a meta-analysis via the Comprehensive software. Standardized mean difference (SMD) was used as a summary statistic. The analysis included a total of 292 individuals with major depressive disorder who received fluoxetine for a period longer than 6 weeks; additionally, IL-1β, IL-6 or TNF-α levels were measured at the end of the antidepressant treatment. The findings were significant revealed decreased levels of the cytokines studied. In conclusion, the pooled data suggest that fluoxetine treatment improved depressive symptomatology by the modulation of pro-inflammatory process such as IL-1β, IL-6 or TNF-α.

OBJECTIVE To evaluate the progression by means of nuclear magnetic resonance of the lesion in the schizophrenia model of lesion of the ventral hippocampal nucleus (LVNH). METHOD Magnetic resonance imaging (MRI) were performed in male Wistar rats, from 8 days postnatal to 139 days, in animals with LNHV and without lesion (sham). The MRI were carried out on a Variant 7 T equipment. The data were analyzed with the Amira software, for a voxel-based morphometric analysis. RESULTS We observed the presence of hypersignals with a significant enhancement in the structures analyzed in the group with LVNH, and greater volume in the lateral ventricles, presenting a larger size of the lesion on day PD96 and significantly reducing on day PD139. CONCLUSIONS We found a cell rearrangement during the progression of the lesion, which could be the effect of the activation of immune cells.

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.

Background Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes. Objective The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides. Methods Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database. Results We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database. Conclusions The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms.

A genetic component is accepted in the etiology of the glioma. Evidence from candidate genes studies and GWAS reveal that CCDC26 gene could increase the risk of glioma. We performed a systematic review and up-to-date meta-analysis to explore if polymorphisms of CCDC26 gene (rs891835, rs6470745, and rs55705857) may be a susceptibility factor in developing glioma. An online search in PubMed, Web of Science, and SCOPUS up to September 2018 was performed. The pooled odds ratios were evaluated by fixed effects model and random effects model. Analyses of the overall sample and ethnic sub-groups were performed. In all the analyses, the allelic, additive, dominant, and recessive models were used. We found an association between all polymorphisms evaluated and an increased risk for glioma in the overall population in all the models studied. In sub-group analysis, we found that rs891835 and rs6470745 increased the risk of glioma in Europeans and Caucasians. On the other hand, the rs891835 polymorphism did not reveal any statistical association in Chinese population. Taken into consideration the limitations of this study, the present findings suggest a possible participation of rs891835, rs6470745, and rs55705857 as risk factors to develop glioma. Furthermore, it is possible that the involvement of CCDC26 variants depends on ethnicity. However, we recommend to perform further studies to have conclusive outcomes.

Background Suicidal behavior may be divided into completed suicide, suicide attempts, and suicidal ideation. It has been suggested that these behaviors represent a continuum and result from the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. Methods The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide) and 419 non-suicide controls. Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. Methylation profile from individuals in the target sample was assessed with the Illumina Infinium Human Methylation EPIC BeadChip. Results We identified 153 differentially methylated sites between individuals with low and high-PRS. From these, 91 sites were hypermethylated and 62 hypomethylated in the high PRS group relative to low PRS group. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment and ATP binding. Discussion To our knowledge, this is the first study integrating polygenic risk scores and DNA methylation in suicidality. Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

Eating disorders (ED) are characterized by disruption of eating behaviour and alteration of food intake. Leptin, is one of the main hormones that modulate food intake and are altered in individuals diagnosed with ED. Genetic risk variants for obesity, like those reported inFTO and ABCA1, have also been associated to ED disorders. The present study aimed to analysed leptin circulating levels and the interaction between obesity-risk variants in FTO and ABCA1, in adolescents diagnosed with ED. A total of 99 individuals diagnosed with ED were genotype using Taqman probes for FTO (rs9939609) and ABCA1 (p.Arg230Cys, rs9282541). Commercial enzyme-linked immunosorbent assays were utilized to determined circulating leptin. Differences in leptin concentration were analysed by t-Student or ANOVA test. Gene-gene interaction were analysed using general estimation equations. Circulating leptin levels differed between the three diagnostic groups, lead by individuals diagnosed with binge eating-disorder. In individuals with more than 3 of episodes of binge-eating per week having the highest leptin levels. Also, we found that carriers of both risk alleles had the highest leptin levels. Our observations found an interaction between FTO rs9969609 and the native American-origin ABCA1 p.Arg230Cys to modulate circulating leptin levels in Mexican adolescents diagnosed with eating-disorders.

Pharmacogenetic analysis has generated translational data that could be applied to guide treatments according to individual genetic variations. However, pharmacogenetic counseling in some mestizo (admixed) populations may require tailoring to different patterns of admixture. The identification and clustering of individuals with related admixture patterns in such populations could help to refine the practice of pharmacogenetic counseling. This study identifies related groups in a highly admixed population-based sample from Mexico, and analyzes the differential distribution of actionable pharmacogenetic variants. A subsample of 1728 individuals from the Mexican Genomic Database for Addiction Research (MxGDAR/Encodat) was analyzed. Genotyping was performed with the commercial PsychArray BeadChip, genome-wide ancestry was estimated using EIGENSOFT, and model-based clustering was applied to defined admixture groups. Actionable pharmacogenetic variants were identified with a query to the Pharmacogenomics Knowledge Base (PharmGKB) database, and functional prediction using the Variant Effect Predictor (VEP). Allele frequencies were compared with chi-square tests and differentiation was estimated by FST. Seven admixture groups were identified in Mexico. Some, like Group 1, Group 4, and Group 5, were found exclusively in certain geographic areas. More than 90% of the individuals, in some groups (Group 1, Group 4 and Group 5) were found in the Central-East and Southeast region of the country. MTRR p.I49M, ABCG2 p.Q141K, CHRNA5 p.D398N, SLCO2B1 rs2851069 show a low degree of differentiation between admixture groups. ANKK1 p.G318R and p.H90R, had the lowest allele frequency of Group 1. The reduction in these alleles reduces the risk of toxicity from anticancer and antihypercholesterolemic drugs. Our analysis identified different admixture patterns and described how they could be used to refine the practice of pharmacogenetic counseling for this admixed population.

Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent an...

espanolAntecedentes: la concurrencia de trastornos por uso de sustancias (TUS) es alta en personas con enfermedades psiquiatricas; Mas importante aun, las personas con ambos trastornos (diagnostico dual) tienen sintomas mas graves. Se han propuesto trastornos psiquiatricos para compartir una susceptibilidad genetica con los TUS. Para explorar esta susceptibilidad genetica compartida, analizamos si alguna de las puntuaciones de riesgo poligenico (PRS) para los trastornos psiquiatricos podria estar asociada al diagnostico dual en pacientes con esquizofrenia (SCZ) o trastorno bipolar (BD). Metodos: Se incluyeron 192 individuos de ascendencia mexicana: 72 con SCZ, 53 con BD y 67 controles no relacionados sin trastornos psiquiatricos. Derivamos calculos de PRS para trastornos del espectro autista, trastorno de deficit de atencion / hiperactivo, BD, depresion mayor y SCZ utilizando estadisticas resumidas de asociacion de genoma previamente publicadas. Resultados: Encontramos que el diagnostico dual tenia una susceptibilidad genetica compartida con el trastorno depresivo mayor (MDD) y SCZ; Ademas, en individuos con BD, PRS podria predecir el diagnostico dual para MDD. Conclusiones: Nuestros resultados refuerzan la nocion de que las personas con diagnostico dual tienen una mayor susceptibilidad genetica a desarrollar ambos trastornos. Sin embargo, se requieren analisis de muestras de mayor tamano para aclarar aun mas como predecir riesgos a traves de PRS dentro de diferentes poblaciones. EnglishBackground: Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). Methods: We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. Results: We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. Conclusions: Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations. (REV INVEST CLIN. 2019;71:321-9)

Background Apolipoprotein E (ApoE) is a glycoprotein that plays an important role in lipid homeostasis at both cerebral and systemic levels. Moreover, the differential distribution of APOE gene alleles among different populations, means that ApoE isoforms could have different effects on lipids metabolism. The present study aims to evaluate the relationship between APOE gene alleles and the lipid profile in a Mexican Amerindian (MA) population. Methods This study included 1997 MA individuals of different ethnicities distributed throughout different states of Mexico. All individuals underwent anthropometric measurements as well as laboratory tests including fasting glucose (FG), total cholesterol (TC), triglycerides, low‐density lipoprotein cholesterol (LDL‐C), and high‐density lipoprotein cholesterol (HDL‐C). TaqMan® probe genotyping assays were used to genotype APOE. The Kruskal–Wallis test was performed to determine the correlation between APOE gene alleles and genotypes and the biochemical variables measured. Results Among the biochemical variables analyzed, only the HDL‐C and LDL‐C levels showed statistical differences (p‐value E3 > E4). This relationship was inversed for LDL‐C levels (E2

espanolAntecedentes: la esquizofrenia (SCZ) y la demencia, a menudo relacionadas, son dos de las enfermedades neuropsiquiatricas mas comunes; Los estudios epidemiologicos han demostrado que los pacientes con SCZ presentan un riesgo 2 veces mayor de demencia en comparacion con los individuos no esquizofrenicos. Exploramos la presencia de variantes geneticas daninas raras y novedosas en pacientes diagnosticados con demencia de inicio tardio de tipo Alzheimer (DAT) o SCZ. Metodos: Incluimos 7 pacientes con DAT y 12 con SCZ y realizamos una secuenciacion dirigida de gran profundidad de 184 genes. Resultados: Encontramos variantes daninas novedosas y raras en 18 genes en estos pacientes mexicanos. Los portadores de estas variantes mostraron fenotipos extremos, incluyendo SCZ resistente al tratamiento o deterioro cognitivo. Ademas, encontramos una variacion en ABCC1 como un posible vinculo entre la psicosis y el deterioro cognitivo. Discusion: Como analisis exploratorio, informamos algunas variaciones interesantes que deberian corroborarse en estudios de mayor tamano de muestra. EnglishBackground: Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer’s type (DAT) or SCZ. Methods: We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes. Results: We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment. Discussion: As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies. (REV INVEST CLIN. 2019;71:246-54)