Genome-wide analyses reveal shared genetic architecture and novel risk loci between opioid use disorder and general cognitive ability

Background Opioid use disorder (OUD), a serious health burden worldwide, is associated with lower cognitive function. Recent studies have demonstrated a negative genetic correlation between OUD and general cognitive ability (COG), indicating a shared genetic basis. However, the specific genetic variants involved, and the underlying molecular mechanisms remain poorly understood. Here, we aimed to quantify and identify the genetic basis underlying OUD and COG. Methods We quantified the extent of genetic overlap between OUD and COG using a bivariate causal mixture model (MiXeR) and identified specific genetic loci applying conditional/conjunctional FDR. Finally, we investigated biological function and expression of implicated genes using available resources. Results We estimated that ~94% of OUD variants (4.8k out of 5.1k variants) also influence COG. We identified three novel OUD risk loci and one locus shared between OUD and COG. Loci identified implicated biological substrates in the basal ganglia. Conclusion We provide new insights into the complex genetic risk architecture of OUD and its genetic relationship with COG.publishedVersio

Genetic and Environmental Factors in Complex Neurodevelopmental Disorders

Complex neurodevelopmental disorders, such as schizophrenia, autism, attention deficit (hyperactivity) disorder, (manic) depressive illness and addiction, are thought to result from an interaction between genetic and environmental factors. Association studies on candidate genes and genome-wide linkage analyses have identified many susceptibility chromosomal regions and genes, but considerable efforts to replicate association have been surprisingly often disappointing. Here, we summarize the current knowledge of the genetic contribution to complex neurodevelopmental disorders, focusing on the findings from association and linkage studies. Furthermore, the contribution of the interaction of the genetic with environmental and epigenetic factors to the aetiology of complex neurodevelopmental disorders as well as suggestions for future research are discussed

Busca por potenciais marcadores genéticos nas fases iniciais da esquizofrenia

Schizophrenia is a severe and disabling psychiatric disorder that affects about 1% of the population. It is a complex disease characterized by the change in multiple genes of susceptibility. Once schizophrenia has been diagnosed, most patients have a poor prognosis, with few returning to normal executive functions after the first psychotic episode (PEP). Thus, the study of individuals at ultra-high risk to develop psychosis (EMR) is of great importance for the understanding of the pathophysiology of schizophrenia, before the establishment of the disease, as well as to find biomarkers related to the transition to schizophrenia. Equally important, the investigation of individuals in their PEP, antipsychotic-naive and before disease progression, is extremely useful for understanding the complexity of schizophrenia and its treatment. Considering that schizophrenia is a chronic disease, its progression and antipsychotic use may be confusing factors in the interpretation of the results of gene expression and DNA methylation. Our main objective was to identify genetic markers of risk, progression and response to treatment in the early stages of schizophrenia by different approaches (genomic, transcriptomic and epigenomic analyses). We investigated 22 subjects at EMR, 66 PEP patients before and after 2 months of treatment with risperidone (PEP-2M), and 67 healthy controls (with no family history or progression of severe psychiatric illness). To better understand the results, we divided this thesis into two studies. In study 1 we evaluated the expression of 12 candidate genes by the TLDA (Taqman Low Density Array) technique in EMR, PEP before treatment and controls. In study 2 we used three large-scale measures (polygenic risk score for schizophrenia, transcriptome and DNA methylome) in controls (N = 60) and in PEP patients before and after risperidone treatment (N = 60). In study 1, we found two differentially expressed genes (UFD1L and MBP), and the UFD1L gene showed an increased expression in the EMR group in relation to the PEP and the controls, suggesting a specific alteration of the individuals at EMR. In study 2, we validated the polygenic risk score (PRS) and demonstrated that this is a measure that can be used effectively in the Brazilian population. In addition, we found positive associations in PEP between PRS and clinical variables, so that the higher the PRS, higher was the impairment. However, these associations are not observed after two months of treatment with risperidone, reinforcing the importance of working with individuals in treatment-free PEP. Finally, we identified some differentially expressed genes and differentially methylated regions related to the disease (when comparing individuals in PEP and controls) and related to the response to treatment (when we followed individuals in PEP before and after risperidone treatment). Using genomic, transcriptomic and epigenomic techniques, we were able to identify genetic markers related to progression and the early stages of schizophrenia in peripheral blood.A esquizofrenia é um transtorno psiquiátrico grave e incapacitante que acomete cerca de 1% da população. Ela é uma doença complexa caracterizada pela alteração em múltiplos genes de suscetibilidade, que atuam em conjunto com processos epigenéticos e ambientais. Uma vez diagnosticada a esquizofrenia, a maioria dos pacientes apresentam um prognóstico não favorável, sendo que poucos retornam às funções executivas normais após o primeiro episódio psicótico (PEP). Desta forma, o estudo de indivíduos em estados mentais de risco para psicose (EMR) é de grande importância para o entendimento da fisiopatologia da esquizofrenia, antes do estabelecimento da doença, bem como para encontrar marcadores relacionados à conversão para esquizofrenia. Igualmente importante, a investigação de indivíduos em seu PEP virgens de tratamento com antipsicóticos e antes da progressão da doença é extremamente útil para a compreensão da complexidade da esquizofrenia e seu tratamento. Considerando-se que a esquizofrenia é uma condição crônica, a progressão da doença e uso de medicação antipsicótica podem ser fatores confundidores na interpretação dos resultados de expressão gênica e de metilação do DNA. Nosso principal objetivo foi identificar em sangue periférico marcadores genéticos de risco, progressão e de resposta ao tratamento nas fases iniciais da esquizofrenia por diferentes enfoques (investigações genômicas, transcriptômicas e epigenômicas). Para tanto, investigamos 22 indivíduos em EMR, 66 pacientes em PEP em dois momentos: antes e após dois meses do início do tratamento com risperidona (FEP-2M), e ainda 67 controles saudáveis (sem histórico familiar ou pregresso de doenças psiquiátricas graves). Para melhor compreensão dos resultados, dividimos esta tese em dois estudos. No estudo 1 avaliamos a expressão de 12 genes candidatos pela técnica de TLDA (Taqman Low Density Array) em EMR, PEP antes do tratamento e controles. No estudo 2 utilizamos três medidas em larga escala: escore poligênico de risco para esquizofrenia (PRS ? do inglês Polygenic Risk Score), transcriptoma e metiloma, todos por microarray em controles (N=60) e em pacientes PEP antes e após o tratamento (N=60). No estudo 1, nós encontramos dois genes diferencialmente expressos (UFD1L e MBP), sendo que o gene UFD1L apresentou uma expressão aumentada no grupo EMR em relação ao PEP e aos controles, sugerindo uma alteração específica dos indivíduos em EMR. No estudo 2, validamos o PRS e demonstramos que essa é uma medida que pode ser utilizada de forma eficaz na população brasileira. Além disso, encontramos associações positivas no PEP entre o PRS e variáveis clínicas, de tal forma que quanto maior o PRS maior é o comprometimento no PEP. Porém, essas associações não são observadas após dois meses de tratamento com risperidona, reforçando a importância em se trabalhar com indivíduos em PEP virgens de tratamento. Por fim, identificamos alguns genes diferencialmente expressos e algumas regiões diferencialmente metiladas relacionadas com a doença (quando comparamos indivíduos em PEP e controles) e com a resposta ao tratamento com a risperidona (quando seguimos indivíduos em PEP antes e após o tratamento). Utilizando técnicas genômicas, transcriptômicas e epigenômicas fomos capazes de identificar em sangue periférico marcadores genéticos relacionados com a progressão e com as fases iniciais da esquizofrenia.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

Climate change and water-related infectious diseases

Background: Water-related, including waterborne, diseases remain important sources of morbidity and mortality worldwide, but particularly in developing countries. The potential for changes in disease associated with predicted anthropogenic climate changes make water-related diseases a target for prevention. Methods: We provide an overview of evidence on potential future changes in water-related disease associated with climate change. Results: A number of pathogens are likely to present risks to public health, including cholera, typhoid, dysentery, leptospirosis, diarrhoeal diseases and harmful algal blooms (HABS). The risks are greatest where the climate effects drive population movements, conflict and disruption, and where drinking water supply infrastructure is poor. The quality of evidence for water-related disease has been documented. Conclusions: We highlight the need to maintain and develop timely surveillance and rapid epidemiological responses to outbreaks and emergence of new waterborne pathogens in all countries. While the main burden of waterborne diseases is in developing countries, there needs to be both technical and financial mechanisms to ensure adequate quantities of good quality water, sewage disposal and hygiene for all. This will be essential in preventing excess morbidity and mortality in areas that will suffer from substantial changes in climate in the future

Quantitative endophenotypes as an alternative approach to understanding genetic risk in neurodegenerative diseases

Endophenotypes, as measurable intermediate features of human diseases, reflect underlying molecular mechanisms. The use of quantitative endophenotypes in genetic studies has improved our understanding of pathophysiological changes associated with diseases. The main advantage of the quantitative endophenotypes approach to study human diseases over a classic case-control study design is the inferred biological context that can enable the development of effective disease-modifying treatments. Here, we summarize recent progress on biomarkers for neurodegenerative diseases, including cerebrospinal fluid and blood-based, neuroimaging, neuropathological, and clinical studies. This review focuses on how endophenotypic studies have successfully linked genetic modifiers to disease risk, disease onset, or progression rate and provided biological context to genes identified in genome-wide association studies. Finally, we review critical methodological considerations for implementing this approach and future directions

Genetics of Obesity: What have we Learned?

Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics and obesity. We comment on the existence of the genetic continuum between monogenic and polygenic forms of obesity that pinpoints the role of genes involved in the central regulation of food intake and genetic predisposition to obesity. We explain how the identification of novel obesity predisposing genes has clarified unsuspected biological pathways involved in the control of energy balance that have helped to understand past human history and to explore causality in epidemiology. We provide evidence that obesity predisposing genes interact with the environment and influence the response to treatment relevant to disease prediction

Inflammation in Posttraumatic Stress Disorder: Dysregulation or Recalibration?

Despite ample experimental data indicating a role of inflammatory mediators in the behavioral and neurobiological manifestations elicited by exposure to physical and psychologic stressors, causative associations between systemic low-grade inflammation and central nervous system inflammatory processes in posttraumatic stress disorder (PTSD) patients remain largely conceptual. As in other stress-related disorders, pro-inflammatory activity may play an equivocal role in PTSD pathophysiology, one that renders indiscriminate employment of anti-inflammatory agents of questionable relevance. In fact, as several pieces of preclinical and clinical research convergingly suggest, timely and targeted potentiation rather than inhibition of inflammatory responses may actually be beneficial in patients who are characterized by suppressed microglia function in the face of systemic low-grade inflammation. The deleterious impact of chronic stress-associated inflammation on the systemic level may, thus, need to be held in context with the - often not readily apparent - adaptive payoffs of low-grade inflammation at the tissue level

Emergence of a recurrent insertion in the N-terminal domain of the {SARS}-{CoV}-2 spike glycoprotein

Tracking the evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through genomic surveillance programs is undoubtedly one of the key priorities in the current pandemic situation. Although the genome of SARS-CoV-2 acquires mutations at a slower rate compared with other RNA viruses, evolutionary pressures derived from the widespread circulation of SARS-CoV-2 in the human population have progressively favored the global emergence, though natural selection, of several variants of concern that carry multiple nonsynonymous mutations in the spike glycoprotein. These are often placed in key sites within major antibody epitopes and may therefore confer resistance to neutralizing antibodies, leading to partial immune escape, or otherwise compensate infectivity deficits associated with other non-synonymous substitutions. As previously shown by other authors, several emerging variants carry recurrent deletion regions (RDRs) that display a partial overlap with antibody epitopes located in the spike N-terminal domain (NTD). Comparatively, very little attention had been directed towards spike insertion mutations prior to the emergence of the B.1.1.529 (omicron) lineage. This manuscript describes a single recurrent insertion region (RIR1) in the N-terminal domain of SARSCoV- 2 spike protein, characterized by at least 49 independent acquisitions of 1–8 additional codons between Val213 and Leu216 in different viral lineages. Even though RIR1 is unlikely to confer antibody escape, its association with two distinct formerly widespread lineages (A.2.5 and B.1.214.2), with the quickly spreading omicron and with other VOCs and VOIs warrants further investigation concerning its effects on spike structure and viral infectivity