E-MAGMA: an eQTL-informed method to identify risk genes using genome-wide association study summary statistics.

MOTIVATION: Genome-wide association studies have successfully identified multiple independent genetic loci that harbour variants associated with human traits and diseases, but the exact causal genes are largely unknown. Common genetic risk variants are enriched in non-protein-coding regions of the genome and often affect gene expression (expression quantitative trait loci, eQTL) in a tissue-specific manner. To address this challenge, we developed a methodological framework, E-MAGMA, which converts genome-wide association summary statistics into gene-level statistics by assigning risk variants to their putative genes based on tissue-specific eQTL information. RESULTS: We compared E-MAGMA to three eQTL informed gene-based approaches using simulated phenotype data. Phenotypes were simulated based on eQTL reference data using GCTA for all genes with at least one eQTL at chromosome 1. We performed 10 simulations per gene. The eQTL-h2 (i.e. the proportion of variation explained by the eQTLs) was set at 1%, 2% and 5%. We found E-MAGMA outperforms other gene-based approaches across a range of simulated parameters (e.g. the number of identified causal genes). When applied to genome-wide association summary statistics for five neuropsychiatric disorders, E-MAGMA identified more putative candidate causal genes compared to other eQTL-based approaches. By integrating tissue-specific eQTL information, these results show E-MAGMA will help to identify novel candidate causal genes from genome-wide association summary statistics and thereby improve the understanding of the biological basis of complex disorders. AVAILABILITY AND IMPLEMENTATION: A tutorial and input files are made available in a github repository: https://github.com/eskederks/eMAGMA-tutorial. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

An integrative systems-based analysis of substance use: eQTL-informed gene-based tests, gene networks, and biological mechanisms.

Genome-wide association studies have identified multiple genetic risk factors underlying susceptibility to substance use, however, the functional genes and biological mechanisms remain poorly understood. The discovery and characterization of risk genes can be facilitated by the integration of genome-wide association data and gene expression data across biologically relevant tissues and/or cell types to identify genes whose expression is altered by DNA sequence variation (expression quantitative trait loci; eQTLs). The integration of gene expression data can be extended to the study of genetic co-expression, under the biologically valid assumption that genes form co-expression networks to influence the manifestation of a disease or trait. Here, we integrate genome-wide association data with gene expression data from 13 brain tissues to identify candidate risk genes for 8 substance use phenotypes. We then test for the enrichment of candidate risk genes within tissue-specific gene co-expression networks to identify modules (or groups) of functionally related genes whose dysregulation is associated with variation in substance use. We identified eight gene modules in brain that were enriched with gene-based association signals for substance use phenotypes. For example, a single module of 40 co-expressed genes was enriched with gene-based associations for drinks per week and biological pathways involved in GABA synthesis, release, reuptake and degradation. Our study demonstrates the utility of eQTL and gene co-expression analysis to uncover novel biological mechanisms for substance use traits.

Comparison of Genome-Wide Association Scans for Quantitative and Observational Measures of Human Hair Curvature.

Previous genetic studies on hair morphology focused on the overall morphology of the hair using data collected by self-report or researcher observation. Here, we present the first genome-wide association study (GWAS) of a micro-level quantitative measure of hair curvature. We compare these results to GWAS results obtained using a macro-level classification of observable hair curvature performed in the same sample of twins and siblings of European descent. Observational data were collected by trained observers, while quantitative data were acquired using an Optical Fibre Diameter Analyser (OFDA). The GWAS for both the observational and quantitative measures of hair curvature resulted in genome-wide significant signals at chromosome 1q21.3 close to the trichohyalin (TCHH) gene, previously shown to harbor variants associated with straight hair morphology in Europeans. All genetic variants reaching genome-wide significance for both GWAS (quantitative measure lead single-nucleotide polymorphism [SNP] rs12130862, p = 9.5 × 10-09; observational measure lead SNP rs11803731, p = 2.1 × 10-17) were in moderate to very high linkage disequilibrium (LD) with each other (minimum r2 = .45), indicating they represent the same genetic locus. Conditional analyses confirmed the presence of only one signal associated with each measure at this locus. Results from the quantitative measures reconfirmed the accuracy of observational measures.

Desastre da Vale: o desafio do cuidado em Saúde Mental e Atenção Psicossocial no SUS / The disaster of Vale in Brazil: Mental Health and Psychosocial Care challenges for SUS

RESUMO Em 25 de janeiro de 2019, a barragem Córrego do Feijão da empresa Vale S.A., em Brumadinho, Minas Gerais, rompeu-se atingindo a área administrativa da empresa e a área rural do entorno, deixando corpos, capacidade produtiva e de subsistência, memórias e trajetórias sob a lama de rejeito de minérios. O rompimento da barragem desencadeou a morte direta de 249 pessoas e deixou 137 pessoas desabrigadas. Este artigo teve como objetivo relatar a experiência da implementação da estratégia de Saúde Mental e Atenção Psicossocial no Sistema Único de Saúde (SUS), considerando os três entes federados, bem como os atores que compuseram a estratégia desde as primeiras horas após o desastre até o final dos primeiros seis meses. Muitos foram os desafios para que o SUS se readaptasse à nova conjuntura, particularmente pela combinação dos seguintes fatores: sofrimento intenso e amplitude das perdas socioafetivas vivenciadas; escassez de emprego e recursos financeiros; consequências ambientais ainda pouco mensuradas; e demanda por ressignificação de uma identidade da comunidade residente. Um trabalho articulado entre o SUS e os diferentes setores, como a educação e a assistência social, mostrou-se importante e primordial, indicando ser necessária a continuidade desses pontos na agenda do SUS.

ABSTRACT On January 25, 2019, the Córrego do Feijão dam of Vale SA, in the city of Brumadinho, Minas Gerais, broke down reaching the company's administrative area and the surrounding rural area, leaving bodies, productive and subsistence capacity, memories and trajectories under the sludge of ore tailings. The rupture of the dam triggered the direct death of 249 people and left 137 people homeless. This article aimed to report the experience of implementing the strategy of Mental Health and Psychosocial Care in the Unified Health System (SUS), considering the three federated entities, as well as the actors that composed the strategy from the first hours after the disaster until the end of the first six months. There were many challenges for the SUS to adapt to the new situation, particularly due to the combination of the following factors: intense suffering and the extent of the socio-affective losses experienced; scarcity of jobs and financial resources; environmental consequences still poorly measured; and demand for the resignification of an identity of the resident community. Articulated work between the SUS and the different sectors, such as education and social assistance, proved to be important and primordial, indicating that it is necessary to continue these points on the SUS agenda.

Gastroprotective effect of the alkaloid boldine: Involvement of non-protein sulfhydryl groups, prostanoids and reduction on oxidative stress.

Boldine is the main alkaloid of Peumus boldus Molina, widely used in the traditional medicine for the treatment of digestive disorders. It is a compound with excellent antioxidant and anti-inflammatory properties already described. Despite the widespread use of P. boldus for digestive disorders treatment, the gastroprotective effect of Boldine remains unknown. Considering the need for new approaches to treat gastric ulcers with fewer side effects than current therapy, this study aimed to investigate the gastroprotective effect of Boldine in mice, as well as the mechanisms underlying this effect. The gastroprotective effect of Boldine was evaluated on gastric ulcer induced by 60% ethanol/0.3 M HCl or indomethacin (100 mg/kg) in mice. Histological analysis and the mucin-like glycoprotein content were evaluated in ethanol-ulcerated tissue, as well as, oxidative stress and inflammatory parameters. The mechanisms involved in the effect of Boldine were evaluated by pretreating mice with NEM (a sulfhydryl group chelator, 10 mg/kg, i.p.), l-NAME (a non-selective nitric oxide synthase inhibitor, 70 mg/kg, i.p.), yohimbine (an alpha-adrenergic receptor antagonist, 2 mg/kg, i.p.) and indomethacin (a cyclooxygenase inhibitor, 10 mg/kg, i.p.). In addition, the in vitro effect of Boldine on H+/K+-ATPase activity was determined. Boldine was able to protect gastric mucosa against the damage induced by ethanol/HCl and indomethacin, as evidenced by reduced lesion area and histological analysis. Moreover, the alkaloid reduced oxidative stress and inflammatory mediators in ethanol-ulcerated tissue, beyond has increased mucin-like glycoprotein amount. Finally, Boldine effect is dependent on non-protein sulfhydryl groups and prostanoids but does not involve the inhibition of H+/K + -ATPase activity, being a promising natural resource for gastric ulcer treatment.

Heritability and GWAS Analyses of Acne in Australian Adolescent Twins.

Acne vulgaris is a skin disease with a multifactorial and complex pathology. While several twin studies have estimated that acne has a heritability of up to 80%, the genomic elements responsible for the origin and pathology of acne are still undiscovered. Here we performed a twin-based structural equation model, using available data on acne severity for an Australian sample of 4,491 twins and their siblings aged from 10 to 24. This study extends by a factor of 3 an earlier analysis of the genetic factors of acne. Acne severity was rated by nurses on a 4-point scale (1 = absent to 4 = severe) on up to three body sites (face, back, chest) and on up to three occasions (age 12, 14, and 16). The phenotype that we analyzed was the most severe rating at any site or age. The polychoric correlation for monozygotic twins was higher (r MZ = 0.86, 95% CI [0.81, 0.90]) than for dizygotic twins (r DZ = 0.42, 95% CI [0.35, 0.47]). A model that includes additive genetic effects and unique environmental effects was the most parsimonious model to explain the genetic variance of acne severity, and the estimated heritability was 0.85 (95% CI [0.82, 0.87]). We then conducted a genome-wide analysis including an additional 271 siblings - for a total of 4,762 individuals. A genome-wide association study (GWAS) scan did not detect loci associated with the severity of acne at the threshold of 5E-08 but suggestive association was found for three SNPs: rs10515088 locus 5q13.1 (p = 3.9E-07), rs12738078 locus 1p35.5 (p = 6.7E-07), and rs117943429 locus 18q21.2 (p = 9.1E-07). The 5q13.1 locus is close to PIK3R1, a gene that has a potential regulatory effect on sebocyte differentiation.

Origin of year-long bean (Phaseolus dumosus Macfady, Fabaceae) from reticulated hybridization events between multiple Phaseolus species.

Background and Aims Improved understanding of the secondary gene pools of crops is essential for advancing genetic gain in breeding programmes. Common bean, Phaseolus vulgaris, is a staple crop with several wild relatives in its secondary gene pool. The year-long bean, P. dumosus, an important crop in Guatemala, is considered particularly closely related to P. vulgaris and a potential source of novel variation. However, the genetic diversity and relationship to other Phaseolus species of P. dumosus remain unclear. Methods We conducted the first comprehensive investigation of P. dumosus genetic diversity using both nuclear and chloroplast genome markers. Our nuclear marker set included over 700 markers present within the Phaseolus DArT (Diversity Arrays Technology) array, which we applied to P. dumosus and other relatives of P. vulgaris (including every secondary gene pool species: P. acutifolius, P. albescens, P. coccineus and P. costaricensis). Key Results Phaseolus dumosus arose from hybridization of P. vulgaris and P. coccineus, followed by at least two later hybridizations with sympatric congener populations. Existing P. dumosus collections have low genetic diversity. Conclusions The under-utilized crop P. dumosus has a complex hybrid origin. Further sampling in the region in which it arose may uncover additional germplasm for introgressing favourable traits into crops within the P. vulgaris gene pool.

Caracterización fisiológica y molecular de aislamientos de Phytophthora infestans de la región andina central colombiana / Physiological and molecular characterization of Phytophthora infestans isolates from the Central Colombian Andean Region

Antecedentes. El tizón tardío, causado por Phytophthora infestans, es una enfermedad devastadora de la papa y el tomate a nivel mundial, y en Colombia también ataca otros cultivos como la uchuva y el tomate de árbol. El conocimiento de la población del patógeno es determinante para el diseño efectivo de estrategias de control. Objetivos. Determinar las características fisiológicas y moleculares de aislamientos colombianos de P. infestans. Métodos. El nivel de resistencia al mefenoxam y al cimoxamil fue evaluado en aislamientos de Cundinamarca y Boyacá. Se estimó su virulencia y se determinó la producción y viabilidad de oosporas en diferentes sustratos con cruces entre aislamientos A1 y el aislamiento colombiano A2. Además, se determinó la diversidad molecular en el gen de avirulencia Avr3a, el gen de la β-tubulina y otros dos genes de copia única con motivo RXLR. Resultados. Los aislamientos colombianos tuvieron la posibilidad de reproducirse sexualmente. Encontramos todos los niveles de sensibilidad al mefenoxam, con el 48% de los aislamientos resistentes. Se detectó una diversidad de razas y a nivel genético la población fue clonal. Conclusiones. Estos resultados ayudarán a optimizar el uso de fungicidas y reducir la resistencia como estrategias de control, además de contribuir al conocimiento de la diversidad de este patógeno(AU)

Background. Late blight, caused by Phytophthora infestans, is one of the most devastating diseases found in potato and tomato crops worldwide. In Colombia it also attacks other important crops: cape gooseberry and tree tomato. The knowledge of the pathogen population is determinant to effectively design control strategies. Aims. To determine the physiological and molecular characteristics of a set of Colombian P. infestans isolates. Methods. Strains isolated from Cundinamarca and Boyacá were examined for the level of resistance to mefenoxam and cymoxanil. Virulence was tested for all strains and crosses between A1 mating type, from different hosts, and the Colombian A2 mating type were tested for the production and viability of oospores in different substrates. Additionally, the molecular diversity of the avirulence gene Avr3a, the β-tubulin gene, and two single copy genes showing RxLR motif, was assessed. Results. We found all levels of mefenoxam sensitivity, with 48% of the strains resistant. A high diversity of races was detected and the population was genetically clonal. Colombian strains had the possibility of sexual reproduction. Conclusions. These results will help in optimizing the use of fungicides and deployment of resistance as control strategies and will contribute to broader studies on diversity of this pathogen(AU)

Physiological and molecular characterization of Phytophthora infestans isolates from the Central Colombian Andean Region.

BACKGROUND: Late blight, caused by Phytophthora infestans, is one of the most devastating diseases found in potato and tomato crops worldwide. In Colombia it also attacks other important crops: cape gooseberry and tree tomato. The knowledge of the pathogen population is determinant to effectively design control strategies. AIMS: To determine the physiological and molecular characteristics of a set of Colombian P. infestans isolates. METHODS: Strains isolated from Cundinamarca and Boyacá were examined for the level of resistance to mefenoxam and cymoxanil. Virulence was tested for all strains and crosses between A1 mating type, from different hosts, and the Colombian A2 mating type were tested for the production and viability of oospores in different substrates. Additionally, the molecular diversity of the avirulence gene Avr3a, the ß-tubulin gene, and two single copy genes showing RxLR motif, was assessed. RESULTS: We found all levels of mefenoxam sensitivity, with 48% of the strains resistant. A high diversity of races was detected and the population was genetically clonal. Colombian strains had the possibility of sexual reproduction. CONCLUSIONS: These results will help in optimizing the use of fungicides and deployment of resistance as control strategies and will contribute to broader studies on diversity of this pathogen.

Gaping of radial and transverse corneal incisions occurring early after CXL.

A 33-year-old woman with corneal ectasia after radial and astigmatic keratotomy had corneal collagen crosslinking with resultant gaping of the inferior incisions (2 radials and 1 transverse) that required suturing. At 6 months, the incisions healed leaving fibrotic scars. Visual acuity, refractions, corneal photographs, and topographic and corneal wavefront measurements are presented. At 2.5 years, the topographic inferior corneal irregularity continued to improve.

Genetic diversity of Phytophthora infestans in the Northern Andean region.

BACKGROUND: Phytophthora infestans (Mont.) de Bary, the causal agent of potato late blight, is responsible for tremendous crop losses worldwide. Countries in the northern part of the Andes dedicate a large proportion of the highlands to the production of potato, and more recently, solanaceous fruits such as cape gooseberry (Physalis peruviana) and tree tomato (Solanum betaceum), all of which are hosts of this oomycete. In the Andean region, P. infestans populations have been well characterized in Ecuador and Peru, but are poorly understood in Colombia and Venezuela. To understand the P. infestans population structure in the Northern part of the Andes, four nuclear regions (ITS, Ras, ß-tubulin and Avr3a) and one mitochondrial (Cox1) region were analyzed in isolates of P. infestans sampled from different hosts in Colombia and Venezuela. RESULTS: Low genetic diversity was found within this sample of P. infestans isolates from crops within several regions of Colombia and Venezuela, revealing the presence of clonal populations of the pathogen in this region. We detected low frequency heterozygotes, and their distribution patterns might be a consequence of a high migration rate among populations with poor effective gene flow. Consistent genetic differentiation exists among isolates from different regions. CONCLUSIONS: The results here suggest that in the Northern Andean region P. infestans is a clonal population with some within-clone variation. P. infestans populations in Venezuela reflect historic isolation that is being reinforced by a recent self-sufficiency of potato seeds. In summary, the P. infestans population is mainly shaped by migration and probably by the appearance of variants of key effectors such as Avr3a.

Characterization of Phytophthora infestans populations in Colombia: first report of the A2 mating type.

Phytophthora infestans, the causal agent of late blight in crops of the Solanaceae family, is one of the most important plant pathogens in Colombia. Not only are Solanum lycopersicum, and S. tuberosum at risk, but also several other solanaceous hosts (Physalis peruviana, S. betaceum, S. phureja, and S. quitoense) that have recently gained importance as new crops in Colombia may be at risk. Because little is known about the population structure of Phytophthora infestans in Colombia, we report here the phenotypic and molecular characterization of 97 isolates collected from these six different solanaceous plants in Colombia. All the isolates were analyzed for mating type, mitochondrial haplotypes, genotype for several microsatellites, and sequence of the internal transcribed spacer (ITS) region. This characterization identified a single individual of A2 mating type (from Physalis peruviana) for the first time in Colombia. All isolates had an ITS sequence that was at least 97% identical to the consensus sequence. Of the 97 isolates, 96 were mitochondrial haplotype IIa, with the single A2 isolate being Ia. All isolates were invariant for the microsatellites. Additionally, isolates collected from S. tuberosum and P. peruviana (64 isolates) were tested for: aggressiveness on both hosts, genotype for the isozymes (glucose-6-phosphate isomerase and peptidase), and restriction fragment length polymorphism fingerprint pattern as detected by RG57. Isolates from S. tuberosum were preferentially pathogenic on S. tuberosum, and isolates from P. peruviana were preferentially pathogenic on P. peruviana. The population from these two hosts was dominated by a single clonal lineage (59 of 64 individuals assayed), previously identified from Ecuador and Peru as EC-1. This lineage was mating type A1, IIa for mitochondrial DNA, invariant for two microsatellites, and invariant for both isozymes. The remaining four A1 isolates were in lineages very closely related to EC-1 (named EC-1.1, CO-1, and CO-2). The remaining lineage (the A2 mating type) had characteristics of the US-8 lineage (previously identified in Mexico, the United States, and Canada). These results have important epidemiological implications for the production of these two crops in Colombia.

Anorexia y bulimia: caracterización y sistematización de la experiencia de intervención de una Clínica de Adolescentes / Anorexy and bulimia: characterization of the experience of intervention of a Clinic of Adolescents

Objetivo: Caracterizar la población de adolescentes con trastornos de la alimentación y presentar el modelo de intervenvión de la Clínica de Adolescentes del Hospital Nacional de Niños. Pacientes: 22 adolescentes seleccionados con el diagnóstico de anorexia o bulimia. Resultados: Se encontraron los siguientes aspectos relevantes: dinámica familiar disfuncional donde sobresale conflictos a nivel del subsistema parental, adolescentes con rendimiento escolar alto previo a la enfermedad, síntomas ansiosos y enfermedad, síntomas ansiosos y preocupación por la imagen corporal desde la infancia, como antecedentes premórbidos. Se da una asociación significativa de la enfermedad con trastornos afectivos, trastornos ansiosos y con conductas de riesgo de los adolescentes. Los trastornos más frecuentemente encontrados a través de exámenes de laboratorio son: anemia, enfermnedad eutiroidea, alteraciones del sodio y de las gonadotropinas hipofisiarias. El modelo de intervención plantado enfatiza sobre el abordaje interdisciplinario y de la necesidad de complementar la intervención con opciones adecuadas para el internamiento. Palabras claves: anorexia, bulimia, equipo interdisciplinario, conductas de riesgo, disfución familiar.