An evolutionary perspective on complex neuropsychiatric disease.

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields the greatest possible range of insight into genes critical to human brain development. In this perspective, we explore some of the relationships between genes, adaptation, and history that can be illuminated by an evolutionary perspective on studies of complex neuropsychiatric disease in diverse populations.

Dendritogenic Potential of the Ethanol Extract from Lippia alba Leaves in Rat Cortical Neurons.

A reduced dendritic complexity, especially in regions such as the hippocampus and the prefrontal cortex, has been linked to the pathophysiology of some neuropsychiatric disorders, in which synaptic plasticity and functions such as emotional and cognitive processing are compromised. For this reason, the identification of new therapeutic strategies would be enriched by the search for metabolites that promote structural plasticity. The present study evaluated the dendritogenic potential of the ethanol extract of Lippia alba, an aromatic plant rich in flavonoids and terpenes, which has been widely used in traditional medicine for its presumed analgesic, anxiolytic, and antidepressant potential. An in vitro model of rat cortical neurons was used to determine the kinetics of the plant's effect at different time intervals. Changes in morphological parameters of the neurons were determined, as well as the dendritic complexity, by Sholl analysis. The extract promotes the outgrowth of dendritic branching in a rapid and sustained fashion, without being cytotoxic to the cells. We found that this effect could be mediated by the phosphatidylinositol 3-kinase pathway, which is involved in mechanisms of neuronal plasticity, differentiation, and survival. The evidence presented in this study provides a basis for further research that, through in vivo models, can delve into the plant's therapeutic potential.

El papel de los esquemas cognitivos y la adversidad infantil en la probabilidad de desarrollar un trastorno depresivo mayor / The role of cognitive schemas and childhood adversity in the likelihood of developing Major Depressive Disorder

Abstract Introduction/objective: Major Depressive Disorder (MDD) is a multifactorial mental health disorder. Stressful events and childhood abuse have been included in different models to explain its etiology. However, little evidence is available on how attributional style and early maladaptive schemas are related to MDD. Method: A retrospective case-control study using a three-stage hierarchical logistic model was conducted to explore the relationship between MDD and psychosocial variables such as childhood adversity, stressful life events, attributional style, and cognitive schemas in a sample of 171 individuals with a current depressive episode and 171 healthy controls. Results: Depression could be predicted by childhood adversity, an attributional style characterized by interpreting stressful events as negative and uncontrollable and the cognitive schemas in impaired autonomy/performance domains and impaired limits. Conclusions: Our results highlight the relevance of identifying cognitive factors, beyond clinical symptoms that could be useful to better understand MDD. These findings may result in better preventive programs and create awareness of the role of cognitive domains in MDD.

Resumen Introducción/objetivo: el trastorno depresivo mayor (TDM) es un trastorno de salud mental de origen multifactorial. Los eventos estresantes y el maltrato infantil se han incluido en diferentes modelos para explicar su etiología. Sin embargo, hay poca evidencia disponible sobre cómo el estilo atribucional y los dominios de esquemas maladaptativos tempranos se relacionan con el TDM. Método: Se realizó un estudio retrospectivo de casos y controles utilizando un modelo logístico jerárquico de tres etapas para explorar la relación entre el TDM y variables psicosociales como la adversidad infantil, los eventos estresantes, el estilo atribucional y los esquemas cognitivos en una muestra de 171 individuos con un episodio depresivo actual y 171 controles sanos. Resultados: La depresión podría predecirse por la adversidad infantil, un estilo atribucional caracterizado por interpretar los eventos estresantes como negativos e incontrolables y los esquemas cognitivos en los dominios de autonomía/desempeño y límites deteriorados. Conclusiones: Nuestros resultados resaltan la relevancia de identificar factores cognitivos, más allá de los síntomas clínicos, que podrían ser útiles para alcanzar una mejor comprensión del trastorno. Estos hallazgos favorecen el diseño de programas de prevención que enfaticen en el rol de los esquemas cognitivos.

Multidimensional Analysis of Major Depression: Association Between BDNF Methylation, Psychosocial and Cognitive Domains.

Major Depression is a complex disorder with a growing incidence worldwide and multiple variables have been associated with its etiology. Nonetheless, its diagnosis is continually changing and the need to understand it from a multidimensional perspective is clear. The purpose of this study was to identify risk factors for depression in a case-control study with 100 depressive inpatients and 87 healthy controls. A multivariate logistic regression analysis was performed including psychosocial factors, cognitive maladaptive schema domains, and specific epigenetic marks (BDNF methylation levels at five CpG sites in promoter IV). A family history of depression, the cognitive schemas of impaired autonomy/performance, impaired limits, other-directedness, and the methylation level of a specific CpG site were identified as predictors. Interestingly, we found a mediating effect of those cognitive schemas in the relationship between childhood maltreatment and depression. Also, we found that depressive patients exhibited hypomethylation in a CpG site of BDNF promoter IV, which adds to the current discussion about the role of methylation in depression. We highlight that determining the methylation of a specific region of a single gene offers the possibility of accessing a highly informative an easily measurable variable, which represents benefits for diagnosis. Following complete replication and validation on larger samples, models like ours could be applicable as additional diagnostic tools in the clinical context.

El papel de la valoración de los sucesos vitales estresantes en el Trastorno Depresivo Mayor / The role of stressful life events appraisal in major depressive disorder

RESUMEN Introducción: El Trastorno depresivo mayor (TDM) es una enfermedad multifactorial en la que, por interacción con diversas variables, se incrementa la vulnerabilidad a padecerla. Diversos modelos han explicado las interacciones, como el de diátesis-estrés. Vivir eventos estresantes no siempre lleva a la aparición del TDM, y se ha planteado que la atribución y la valoración de los eventos estresantes podrían ser un mejor predictor de la aparición de los síntomas. Objetivo: Determinar la asociación y el poder predictivo de la frecuencia y la valoración de eventos vitales estresantes en la presencia de sintomatología del TDM. Métodos: Estudio de casos y controles con 120 pacientes psiquiátricos y 120 personas de la población general. Se utilizó una entrevista clínica estructurada y el Cuestionario de Sucesos Vitales de Sandín y Chorot. Los datos se analizaron con pruebas no paramétricas y regresión logística binaria. Resultados: El grupo de casos obtuvo significativamente más altos en afecto negativo, frecuencia de eventos estresantes, nivel de estrés percibido, valoración negativa de la situación y percepción de no control. El modelo de regresión logística binaria indicó que la baja percepción de control frente al evento estresante es el factor más determinante, seguido por la evaluación negativa del evento. Conclusiones: Las atribuciones realizadas sobre los eventos estresantes son determinantes en la presentación del TDM, en especial la valoración del control percibido frente a los sucesos vitales, en concordancia con los modelos etiológicos del TDM de diátesis cognitiva al estrés.

ABSTRACT Introduction: Major depressive disorder (MDD) is a multifactorial disease in which, due to the interaction of several variables, the vulnerability of suffering from it increases. Several models, such as the diathesis-stress model, have explained these interactions. However, experiencing stressful events does not always lead to the development of MDD, and the attribution and appraisal of stressful events contributing to further development of depression symptoms has been considered as a possible explanation. Objective: To determinate the association and the predictive power of the frequency and appraisal of stressful life events to predict MDD symptomatology. Methods: Case-control study with 120 psychiatric patients and 120 people from the general population. A structured clinical interview and the life events questionnaire (Sandín and Chorcot) were used to evaluate the sample. The data were analysed with non-parametric tests and binary logistic regression. Results: The psychiatric patients reported significantly higher levels of negative affect, frequency of stressful life events, perceived stress, negative appraisal of the situation and lack of perceived control. The binary logistic regression model indicated that poor perception of control of the stressful event is the most determining factor, followed by negative evaluation of the situation. Conclusions: The attributions that are made regarding a stressful event are variables that predict MDD, specifically the assessment of the perceived control over the situation. These results concur with the aetiological models of MDD, such as the cognitive diathesis-stress model.

The role of stressful life events appraisal in major depressive disorder. / El papel de la valoración de los sucesos vitales estresantes en el Trastorno Depresivo Mayor.

INTRODUCTION: Major depressive disorder (MDD) is a multifactorial disease in which, due to the interaction of several variables, the vulnerability of suffering from it increases. Several models, such as the diathesis-stress model, have explained these interactions. However, experiencing stressful events does not always lead to the development of MDD, and the attribution and appraisal of stressful events contributing to further development of depression symptoms has been considered as a possible explanation. OBJECTIVE: To determinate the association and the predictive power of the frequency and appraisal of stressful life events to predict MDD symptomatology. METHODS: Case-control study with 120 psychiatric patients and 120 people from the general population. A structured clinical interview and the life events questionnaire (Sandín and Chorcot) were used to evaluate the sample. The data were analysed with non-parametric tests and binary logistic regression. RESULTS: The psychiatric patients reported significantly higher levels of negative affect, frequency of stressful life events, perceived stress, negative appraisal of the situation and lack of perceived control. The binary logistic regression model indicated that poor perception of control of the stressful event is the most determining factor, followed by negative evaluation of the situation. CONCLUSIONS: The attributions that are made regarding a stressful event are variables that predict MDD, specifically the assessment of the perceived control over the situation. These results concur with the aetiological models of MDD, such as the cognitive diathesis-stress model.

Outlining the Ancestry Landscape of Colombian Admixed Populations.

The ancestry of the Colombian population comprises a large number of well differentiated Native communities belonging to diverse linguistic groups. In the late fifteenth century, a process of admixture was initiated with the arrival of the Europeans, and several years later, Africans also became part of the Colombian population. Therefore, the genepool of the current Colombian population results from the admixture of Native Americans, Europeans and Africans. This admixture occurred differently in each region of the country, producing a clearly stratified population. Considering the importance of population substructure in both clinical and forensic genetics, we sought to investigate and compare patterns of genetic ancestry in Colombia by studying samples from Native and non-Native populations living in its 5 continental regions: the Andes, Caribe, Amazonia, Orinoquía, and Pacific regions. For this purpose, 46 AIM-Indels were genotyped in 761 non-related individuals from current populations. Previously published genotype data from 214 Colombian Natives from five communities were used for population comparisons. Significant differences were observed between Native and non-Native populations, among non-Native populations from different regions and among Native populations from different ethnic groups. The Pacific was the region with the highest African ancestry, Amazonia harboured the highest Native ancestry and the Andean and Orinoquían regions showed the highest proportion of European ancestry. The Andean region was further sub-divided into 6 sub-regions: North East, Central West, Central East, West, South West and South East. Among these regions, the South West region showed a significantly lower European admixture than the other regions. Hardy-Weinberg equilibrium and variance values of ancestry among individuals within populations showed a potential stratification of the Pacific population.

HLA-DRB1*14 is a protective allele for multiple sclerosis in an admixed Colombian population.

OBJECTIVE: The aim of this study was to determine ancestry informative markers, mitochondrial DNA haplogroups, and the association between HLA-DRB1 alleles and multiple sclerosis (MS) in a group of patients from Bogotá, Colombia. METHODS: In this case-control study, genomic DNA was isolated and purified from blood samples. HLA-DRB1 allele genotyping was done using PCR. Mitochondrial hypervariable region 1 was amplified and haplogroups were determined using HaploGrep software. Genomic ancestry was estimated by genotyping a panel of ancestry informative markers. To test the association of HLA polymorphisms and MS, we ran separate multivariate logistic regression models. Bonferroni correction was used to account for multiple regression tests. RESULTS: A total of 100 patients with MS (mean age 40.4 ± 12 years; 70% females) and 200 healthy controls (mean age 37.6 ± 11 years; 83.5% females) were included in the analysis. Ancestry proportions and haplogroup frequencies did not differ between patients and controls. HLA-DRB1*15 was present in 31% of cases and 13.5% of controls, whereas HLA-DRB1*14 was present in 5% of cases and 15.5% of controls. In the multivariate model, HLA-DRB1*15 was significantly associated with MS (odds ratio [OR] = 3.05, p < 0.001), whereas HLA-DRB1*14 was confirmed as a protective factor in our population (OR = 0.16, p = 0.001). CONCLUSIONS: This study provides evidence indicating that HLA-DRB1*15 allele confers susceptibility to MS and HLA-DRB1*14 allele exerts resistance to MS in a highly admixed population. This latter finding could partially explain the low prevalence of MS in Bogotá, Colombia.

Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders.

Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian-South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding.

Modeling of the hypothalamic-pituitary-adrenal axis-mediated interaction between the serotonin regulation pathway and the stress response using a Boolean approximation: a novel study of depression.

Major depressive disorder (MDD) is a multifactorial disorder known to be influenced by both genetic and environmental factors. MDD presents a heritability of 37%, and a genetic contribution has also been observed in studies of family members of individuals with MDD that imply that the probability of suffering the disorder is approximately three times higher if a first-degree family member is affected. Childhood maltreatment and stressful life events (SLEs) have been established as critical environmental factors that profoundly influence the onset of MDD. The serotonin pathway has been a strong candidate for genetic studies, but it only explains a small proportion of the heritability of the disorder, which implies the involvement of other pathways. The serotonin (5-HT) pathway interacts with the stress response pathway in a manner mediated by the hypothalamic-pituitary-adrenal (HPA) axis. To analyze the interaction between the pathways, we propose the use of a synchronous Boolean network (SBN) approximation. The principal aim of this work was to model the interaction between these pathways, taking into consideration the presence of selective serotonin reuptake inhibitors (SSRIs), in order to observe how the pathways interact and to examine if the system is stable. Additionally, we wanted to study which genes or metabolites have the greatest impact on model stability when knocked out in silico. We observed that the biological model generated predicts steady states (attractors) for each of the different runs performed, thereby proving that the system is stable. These attractors changed in shape, especially when anti-depressive drugs were also included in the simulation. This work also predicted that the genes with the greatest impact on model stability were those involved in the neurotrophin pathway, such as CREB, BDNF (which has been associated with major depressive disorder in a variety of studies) and TRkB, followed by genes and metabolites related to 5-HT synthesis.

[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. / Una mirada al albinismo óculo-cutáneo: reporte de mutaciones en el gen TYR en cinco individuos colombianos.

INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.