Suicidal ideation and planning among Mexican adolescents are associated with depression polygenic risk scores.

Suicide is a major public health problem in Mexico and around the world. Genetic predisposition for major depressive disorder (MDD) has been associated with increased risk for suicidal behaviors (SB) in populations of European ancestry (EA). Here, we examine whether MDD polygenic risk scores (MDD PRS), derived from a genome-wide association study involving EA individuals, predict SB, including ideation, planning, and attempt, among Mexican youth using a longitudinal design. At baseline, participants (N = 1,128, 12-17 years, 55% women) were interviewed and genotyped as part of a general population survey on adolescent mental health. Eight years later, they were recontacted for a follow up visit (N = 437, 20-25 years, 63% women). At both assessments, individuals reported on their engagement in SB within the past year. MDD PRS were significantly positively associated with SB, particularly suicide ideation and planning during adolescence, accounting for ~4-5% of the variance in these outcomes. In contrast, associations between MDD PRS and SB during young adulthood did not reach statistical significance. Our results suggest that increased genetic liability for depression increased risk for SB, particularly during adolescence, expanding our knowledge of the genetic underpinnings of SB.

Genetic and epigenetic regulation of the brain-derived neurotrophic factor in the central nervous system.

The BDNF is required for the development and proper function of the central nervous system, where it is involved in a variety of neural and molecular events relevant to cognition, learning, and memory processes. Although only a functional mature protein is synthesized, the human BDNF gene possesses an extensive structural complexity, including the presence of multiple promoters, splicing events, and 3´UTR poly-adenylation sites, resulting in an intricate transcriptional regulation and numerous messengers RNA. Recent data support specific cellular roles of these transcripts. Moreover, a central role of epigenetic modifications on the regulation of BDNF gene transcription is also emerging. The present essay aims to summarize the published information on the matter, emphasizing their possible implications in health and disease or in the treatment of different neurologic and psychiatric disorders.

Associations of externalizing polygenic scores with externalizing disorders among Mexican youth.

Several studies have examined the association of externalizing polygenic scores (PGS) with externalizing symptoms in samples of European ancestry. However, less is known about the associations of externalizing polygenic vulnerability in relation to phenotypic externalizing disorders among individuals of different ancestries, such as Mexican youth. Here, we leveraged the largest genome-wide association study on externalizing behaviors that included over 1 million individuals of European ancestry to examine associations of externalizing PGS with a range of externalizing disorders in Mexican adolescents, and investigated whether adversity exposure in childhood moderated these associations. Participants (N = 1064; age range 12-17 years old; 58.8% female) were adolescents recruited for a general population survey on adolescent mental health in the Mexico City Metropolitan region and were genotyped. Childhood adversity exposure and externalizing disorders, specifically attention-deficit hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, and substance use disorder, were assessed via the computer-assisted World Mental Health Composite International Diagnostic Interview for adolescents. A greater externalizing PGS was associated with a greater odds of any externalizing disorder (OR = 1.29 [1.12, 1.48]; p < 0.01) and ADHD (OR = 1.40 [1.15, 1.70]; p < 0.01) in the whole sample, and in females in particular. There were no main effects of the externalizing PGS on conduct disorder, oppositional defiant disorder, or substance use disorder, nor did adversity exposure moderate these associations. Our results suggest that greater genetic propensity for externalizing disorders is associated with increased odds of any externalizing disorders and ADHD among Mexican adolescents, furthering our understanding of externalizing disorder manifestation in this population.

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

CRISPR/Cas9 Genome Editing Approaches for Psychiatric Research.

Currently, genome editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), are predominantly used to model genetic diseases. This genome editing system can correct point or frameshift mutations in risk genes. Here, we analyze and discuss the advantages of genome editing, its current applications, and the feasibility of the CRISPR/Cas9 system in research on psychiatric disorders. These disorders produce cognitive and behavioral alterations and their etiology is associated with polygenetic and environmental factors. CRISPR/Cas9 may reveal the biological mechanisms of psychiatric disorders at a basic research level, translating a suitable clinical approach for use in the diagnosis and treatment of psychiatric disorders. Genetic diagnosis and treatment for these disorders have not yet been fully established in psychiatry due to the limited understanding of their heterogeneity and polygenicity. We discuss the challenges and ethical issues in using CRISPR/Cas9 as a tool for diagnosis or gene therapy.

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders.

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Cognitive impairment in the co-occurrence of alcohol dependence and major depression: neuropsychological assessment and event-related potentials analyses.

To evaluate the putative detrimental effect of Major Depressive Disorder (MDD) on the cognitive impairment associated with Alcohol Dependence (AD), we contrasted the neuropsychological profile and behavioral responses of AD subjects, MDD individuals, and in those with a co-occurring AD-MDD diagnosis (DD). Patients and healthy subjects completed a comprehensive neuropsychological battery and were recorded for P200, P300, and N450 event-related potentials during memory and Stroop tasks. AD subjects exhibited a generalized detrimental neuropsychological performance; in contrast, in MDD individuals, impairment was limited to discrete domains. Notably, the deficits were distinctive in DD cases. A P200 increased amplitude in MDD, a decrease in P300 amplitude in AD, and increased latency of P300 in DD patients were the overt electrophysiological abnormalities identified. Dual patients also exhibited a distinct pattern of behavioral responses, particularly apparent during high-demand cognitive tasks. Specific ERP adjustments were associated with the short-term fluoxetine treatment in DD and MDD subjects; the SSRI also improved altered baseline performance in learning and cognitive flexibility in DD subjects. In conclusion, the neuropsychological and behavioral alterations detected in the co-occurrence of AD-MDD did not seem to be merely the sum of the negative contributions of the independent disorders.

Excessive daytime sleepiness in depressed women.

Excessive daytime sleepiness (EDS) is a symptom with high public health importance. Within psychiatric settings, depression is the most significant risk factor for EDS; however, this relationship has not been clearly detailed. The aim of this study was to describe the quality of sleep of depressed patients with and without EDS and to investigate the association between EDS and depression severity. A cross-sectional study with 78 female depressed outpatients (34.17 +/- 11.37 years; range 18-60) was performed. The Epworth Sleepiness Scale, the Athens Insomnia Scale, the Pittsburgh Sleep Quality Index, and the Hamilton Rating Scale for Depression (HRSD) were administered. Patients were classified in two groups: with (43.5%) and without (56.5%) EDS. There were no differences with regard to comorbidity, socio-demographic (except for employment), or HRSD variables. The two groups were homogeneous in sleep patterns, with no difference in quality or sleep efficiency. EDS was not associated with reduced sleep efficiency or severity of depressive symptoms. Limitations of the present study include the small sample size and the use of self-report measurements. These results offer valuable information to clinicians in the sense of the need to deeply investigate the etiology of EDS before attributing it to bad sleep quality or depression severity.

CRISPR/Cas9 genome editing approaches for psychiatric research

Currently, genome editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), are predominantly used to model genetic diseases. This genome editing system can correct point or frameshift mutations in risk genes. Here, we analyze and discuss the advantages of genome editing, its current applications, and the feasibility of the CRISPR/Cas9 system in research on psychiatric disorders. These disorders produce cognitive and behavioral alterations and their etiology is associated with polygenetic and environmental factors. CRISPR/Cas9 may reveal the biological mechanisms of psychiatric disorders at a basic research level, translating a suitable clinical approach for use in the diagnosis and treatment of psychiatric disorders. Genetic diagnosis and treatment for these disorders have not yet been fully established in psychiatry due to the limited understanding of their heterogeneity and polygenicity. We discuss the challenges and ethical issues in using CRISPR/Cas9 as a tool for diagnosis or gene therapy.

Impaired control in heavy drinking and its association with alcohol craving and alcohol use disorder severity / Deterioro del control en el consumo excesivo de alcohol y su asociación con el deseo de consumo y la gravedad del trastorno por uso de alcohol

Abstract Introduction Impaired control over drinking has been frequently cited in diverse theoretical descriptions regarding harmful alcohol use and is considered a DSM criterion for alcohol use disorder. Differences in the frequency of endorsement of impaired control have been viewed as a reflection of the severity of the problem. Moreover, it has been posited that the ability to place a limit on alcohol consumption may be mediated through enhanced craving. Objective In this study, we addressed the relationship between impaired control, self-reported craving, and alcohol dependence severity among heavy drinkers. Method We conducted a latent class analysis of impaired control dimensions (perceived control, failed control, and attempted control) of 208 heavy drinkers. To determine whether the identified classes could represent different forms of severity of the disorder, the best-fit model was contrasted with scores on the Alcohol Dependence Scale. Furthermore, we assessed the relationship between impaired control criteria (using the Impaired Control Scale [ICS]) with alcohol craving. Results We identified a three-class solution based on impaired control severity. A graded increase of the craving scores and alcohol severity among the three classes was also identified. Only the ICS items comprising perceived control and partially those related to failed control, but not those evaluating attempted control, distinguished the gradient among the latent classes. Discussion and conclusion This study provides further support of the proposal of a unidimensional continuum of severity among heavy drinkers and strengthens the theoretical relationship between impaired control and alcohol craving.

Resumen Introducción El deterioro del control sobre el consumo del alcohol se ha mencionado con frecuencia en diversas descripciones teóricas relativas al uso nocivo y es un criterio clínico del DSM para el trastorno por uso de alcohol. Las diferencias en la frecuencia con que se admite el deterioro del control se han considerado como un reflejo de la gravedad del problema. Además, se ha postulado que la capacidad de poner un límite al consumo de alcohol puede estar mediada por el deseo de consumirlo (craving). Objetivo En este estudio se abordó la relación entre el deterioro del control, el autoreporte del craving y la gravedad de la dependencia del alcohol en un grupo de bebedores fuertes. Método Se realizó un análisis de clases latentes usando las dimensiones del deterioro del control (control percibido, control fallido e intento de control) de 208 bebedores fuertes. Para determinar si las clases identificadas podían representar diferentes formas de gravedad del trastorno se contrastó el modelo más adecuado con las puntuaciones de la Escala de Dependencia del Alcohol. Además, se evaluó la relación entre los criterios de deterioro del control (utilizando la Escala de Control Deficiente, ECD) y el craving. Resultados Identificamos una solución de tres clases basada en la gravedad del deterioro de control. En esa solución se identificó una relación con el aumento graduado de las puntuaciones de craving y la gravedad de la dependencia entre las clases. Sólo los elementos de la ECD que comprenden el control percibido y parcialmente los relacionados con el control fallido, pero no los que evalúan el intento de control, distinguieron el gradiente entre las clases latentes. Discusión y conclusión Este estudio proporciona más apoyo a la propuesta de un continuum unidimensional de gravedad entre los usuarios de alcohol y refuerza la relación teórica entre el fenómeno de deterioro del control y el craving.

BDNF Met66 modulates the cumulative effect of psychosocial childhood adversities on major depression in adolescents.

BACKGROUND: The interplay among lifetime adversities and the genetic background has been previously examined on a variety of measures of depression; however, only few studies have focused on major depression disorder (MDD) in adolescence. METHODS: Using clinical data and DNA samples from mouthwash gathered from an epidemiological study on the prevalence of mental disorders in youths between 12 and 17 years old, we tested the statistical interaction between a set of psychosocial adversities experienced during childhood (CAs) with two common polymorphisms in the brain-derived neurotrophic factor (BDNF) (Val66Met) and SLC6A4 (L/S) genes on the probability of suffering MDD in adolescence. RESULTS: Genotype or allele frequencies for both polymorphisms were similar between groups of comparison (MDD N = 246; controls N = 270). The CAs factors: Abuse, neglect, and family dysfunctions; parental maladjustment, parental death, and to have experienced a life-threatening physical illness were predictors of clinical depression in adolescents. Remarkably, the cumulative number of psychosocial adversities was distinctly associated with an increase in the prevalence of depression but only in those Val/Val BDNF individuals; while the possession of at least a copy of the BDNF Met allele (i.e., Met +) was statistically linked with a "refractory" or resilient phenotype to the noticeable influence of CAs. CONCLUSION: Liability or resilience to develop MDD in adolescence is dependent of a complex interplay between particular environmental exposures and a set of plasticity genes including BDNF. A better understanding of these factors is important for developing better prevention and early intervention measures.

3111T/C clock gene polymorphism is not associated with sleep disturbances in untreated depressed patients.

Sleep patterns, frequently altered in depression, have been hypothesized to be under genetic control. The circadian locomotor output cycles kaput (CLOCK) T3111C variant has been studied in association with sleep disturbances in depressed patients. The aim of this study was to investigate possible effects of T3111C CLOCK on insomnia, daytime sleepiness, sleep quality, and depression severity in a sample of 100 major depressive disorder patients. Inclusion criteria were: major depressive disorder, drug-free for any antidepressant and/or benzodiazepines for at least four weeks previously to the study, and a minimum score of >17 on the Hamilton Rating Scale for Depression. The Morningness-Eveningness Questionnaire, Epworth Sleepiness Scale, Athens Insomnia Scale, and Pittsburgh Sleep Quality Index were applied. No significant difference was found concerning genotype or allele groups and Hamilton Rating Scale for Depression items or clusters. No difference was found between genotypes and comorbidity, chronotype distribution, Epworth Sleepiness Scale, Athens Insomnia Scale, or Pittsburgh Sleep Quality Index total scores. Overall, the present findings did not support the hypothesis of an effect of the T3111C CLOCK variant on sleep disturbances in major depressive disorder. Further analysis of clock machinery will clarify the contribution of clock genes to the maintenance of mental health.

Depressive symptomatology is influenced by chronotypes.

BACKGROUND: Rhythm disturbances are a frequent clinical manifestation of depression. In recent years a possible relationship between depression and chronotypes has emerged. Specifically eveningness has been proposed as vulnerability factor. The aim of this study was to describe sleep features of depressed patients according to chronotypes and to explore possible associations with the clinical features of depressive episodes. METHODS: 100 patients diagnosed with Major Depressive Disorder according to the Mini International Neuropsychiatric Interview (MINI) were included (age: 34+/-11.74, range: 18-60 years; female/male:79/21). At admission the Hamilton Rating Scale for Depression (HRSD) was administered. Patients were also administered the Morningness-Eveningness Questionnaire (MEQ), the Epworth Sleepiness Scale, the Athens Insomnia Scale and the Pittsburgh Sleep Quality Index. RESULTS: According to MEQ scores patients were classified in three groups: a) eveningness (n=18), b) neither (n=61) and c) morningness type (n=21). The age was different among chronotypes, being morningness-type patients older. The eveningness-type group showed higher scores in suicidal thoughts, more impaired work and activities, higher paranoid symptoms, higher scores on the anxiety cluster (HRSD), while the morningness-type group showed lower proportion of melancholic symptoms (MINI). We did not find association between sleep parameters and specific chronotypes. LIMITATIONS: The relatively small sample size and the concurrent assessment of chronotypes and depression may have biased our findings. CONCLUSIONS: Our data suggest the idea that chronotypes have an impact on depressive episodes features, with higher severity for the eveningness-type.

Distribution of apolipoprotein E alleles in coras and huicholes from Nayarit and Nahuas and Mestizos from Veracruz, Mexico.

We report allele frequencies for the most common polymorphism of the APOE gene in Mexican individuals from two regions not previously described: Coras and Huicholes from Nayarit, and Nahuas and mestizos from Veracruz. We also report APOE allele frequencies for inhabitants of Mexico City. These descriptive data underscore the allelic heterogeneity for this particular locus in Mexico.

Datos sobre la validez y confiabilidad de la Symptom Check List 90 (SCL 90) en una muestra de sujetos mexicanos

resumen está disponible en el texto completo

Abstract: A genetic epidemiology paradigm employed in the identification of genes associated with a disease depends on the comparison of the frequency of common genetic variants between groups of individuals who possess a relevant trait versus those who do not show the trait (i.e., cases vs. controls genetic association study). The adequate classification of groups of contrast is therefore of seminal importance for the identification of relevant genes. For psychiatric disorders, the careful clinical evaluation of particular symptoms is the basis for the classification of the "affected or disease group". However, in many psychiatric genetics studies the constitution of the "control" or "normal" group has been based only on the absence of an overt expression of symptoms, where no particular emphasis is given to the symptom evaluation to exclude the phenotype. The use of psychometric instruments can help to assess some behavioral traits of clinical relevance. In turn, these assessments could help in the diagnosis, prognosis and treatment of disorders. Moreover, quantitative assessments let determine if these traits belong to the normal range of variation in a population or could be a deviation of the trend. The Symptom Checklist 90 (SCL90) is a 90-item self-report inventory that assesses the level of distress recently experienced by the subject. It is comprised of nine dimensions: somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism and a General Severity Index (GSI). Although the SCL 90 is a well-accepted and widely used instrument in research and clinical practice in many countries, we found a scarcity of relevant studies for Latin America and a lack of normative data for Mexican populations. The aim of the present report was to evaluate the reliability and construct validity of the SCL 90. Method Subjects A Spanish translation of the original SCL90 English version was administered to a group of 228 subjects, comprised by relatives of patients, members of a family parents association, medical and paramedical staff, and college students. The SCL90 was included within a battery of clinical and psychometric assessments of individuals participating at ongoing research protocols on the genetics of personality and creativity. An additional group of 30 ambulatory psychiatric patients from the Instituto Nacional de Psiquiatría Ramón de la Fuente (INPRF) was also analyzed. The instrument was applied by experienced qualified personal. Statistical analyses Statistical analyses were performed using SYSTAT 8.0. Reliability was evaluated by assessing the response consistency obtained from those items with similar questions. The Cronbach's alpha coefficient was used as the measure of the internal consistency for all nine subscales for this purpose. Construct validity was assessed using two complementary criteria: a) evaluating pre-conceptual hypotheses and b) analysing psychometric data. In the first case, and based on previous reports showing that the level of distress is a function of social-demographic, gender and clinical status, it was hypothesized that the mean scores should be higher in women, younger people and individuals affected with a psychiatric condition. ANOVA and F statistics were computed using the mean scores and standard deviations for the nine dimensions and GSI. In addition, the extent of correlation between individual items and its own subscale dimension should be higher than the other subscales, and the level of correlation between each item and the GSI should be positive. In this case, a Spearman rank correlation matrix was constructed for the SCL90 items and the nine subscales, as well as the GSI. Results Internal consistency All but two of the nine SCL90 dimensions showed good internal consistency values (Cronmbach's alphas >0.7-0.85); with only hostility and paranoid ideation subscales reaching an acceptable value (>0.6-<0.7). The overall Cronbach's alpha score obtained for the GSI was 0.96. Construct validity Fifty-six of the SCL90 items showed a Spearman rank correlation coefficient value (r > 0.5), 23 items showed a moderate value (r >0.25 and <0.5), and only one item showed a weak correlation with its own scale (r =0.2). Only in one case (item 80) the highest correlation value did not correspond with its particular dimension. Mean scores for all of the nine dimensions of the SCL90, as well as the GSI, were higher in women compared to men, and in subjects < 25 years old. The ANOVA showed statistically significant differences (p< 0.01) for somatization, depression, obsessive-compulsive, interpersonal sensitivity, anxiety, hostility dimensions as well as for the GSI. Likewise, an ANCOVA, using age as a covariable, showed an age effect for the last five dimensions (p < 0.005), and in lesser degree for paranoid ideation (p =0.014). Likewise, both men and women patients populations showed higher scores for each dimension compared to general population. Comparison between Mexican and Argentine populations Independent sample t test showed meaningful differences for three scales (obsessive compulsive, interpersonal sensitivity, anxiety, as well as for the GSI) in men and women. Somatization was statistically different only for women from Argentina. Percentiles calculated for each one of all dimensions and the GSI showed a general tendency to be higher for the Mexican population compared with data from Argentina. Discussion The SCL90 is a self-report inventory where the subject reflects his/her perception about the degree of distress that he/she is experiencing. It is used by clinicians and researchers to gather information about the mental health of subjects. In the mental health field, the SCL90 has been employed world-wide to monitor the quality of the medical-psychological interventions, as well as a screening tool to identify psychopathology symptoms. We examined certain psychometric properties of the Spanish version of the SCL90, as there is a lack of normative data for Mexico. The internal consistency reliability for the scale as a whole and for individuals subscales was in general terms adequate for the group of individuals examined. Validity was assured throughout the confirmation of expected differences of groups of comparison and by the good correlation agreement among specific items and their particular dimensions. Compared to the only Latin American study, the mean scores for Mexican population were higher than in Argentina and even higher compared with the USA normative sample. Among others putative factors, translation issues (e.g. use of double negative sentences) and /or cross-cultural differences (e.g. demographic characteristics, socioeconomic differences) should be taken into account to explain these differences; therefore caution should be applied when comparing data of different populations. Among the limitations of this study we must include the analysis of a non-population sample of modest size. Nonetheless, we can conclude that the SCL90 inventory shows good psychometric attributes that may be useful for research and/or clinical purposes. Percentiles rank data can be used as a starting reference for others researchers interested in evaluating in a fast and simple way the psychological distress status of a particular individual, underlying the necessity of developing on a short-term basis normative data for the Mexican population.