Exploring the molecular pathways linking sleep phenotypes and POGZ-associated neurodevelopmental disorder.

Pogo transposable element-derived protein with ZNF domain (POGZ) gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these patients, yet the biological pathways which link sleep traits to the POGZ-associated syndrome remain unclear. We screened for sleep implications among individuals with causative POGZ variants previously described. Sleep disturbances were observed in 52% of patients, and being obese was not observed as a risk factor for sleep problems. Next, we identified genes associated with sleep-associated traits among the POGZ regulatory targets, aiming to uncover the molecular pathways that, when disrupted by POGZ loss of function, contribute to the aetiology of sleep phenotypes in these patients. The intersect between POGZ targets and sleep-related genes was used in a pathway enrichment analysis. Relevant pathways among these overlapping genes are involved in the regulation of circadian rhythm, tau protein binding, ATPase activator activity. This study may represent the beginning for novel functional investigations on shared molecular mechanisms between sleep disturbances and rare developmental syndromes related to POGZ and its regulatory targets.

The relationship between neurodevelopmental transcriptional programs and insomnia: From Rubinstein-Taybi syndrome into energy metabolism.

Neurodevelopmental disorders (NDD) are characterized by cognitive, emotional, and/or motor skills impairment since childhood, and sleep disturbances are a common comorbidity. Rubinstein-Taybi syndrome (RSTS), a rare genetic syndrome associated with NDD, is caused by CREBBP haploinsufficiency. This gene encodes an acetyltransferase with crucial role on the establishment of transcriptional programs during neurodevelopment. Although insomnia has been reported in RSTS patients, the convergent mechanisms between this sleep disturbance and CREBBP loss-of-function are not fully understood. We tested weather the genetic architecture underlying CREBBP regulatory targets and insomnia-associated genes is significantly shared. We then identified the biological pathways enriched among these shared genes. The intersection between CREBBP regulatory targets and genes associated with insomnia included 7 overlapping genes, indicating significantly more overlap than expected by chance. An over-representation analysis on these intersect genes identified pathways related to mitochondrial activity. This finding indicates that the transcriptional programs established by CREBBP might impact insomnia-related biological pathways through the modulation of energy metabolism. The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between insomnia and CREBBP regulatory targets.

Endocrine and Epigenetic Regulation as Common Pathways Underlying the Genetic Basis of Sleep Traits and Longevity.

The amount of sleep needed over one's lifespan is age dependent and not sleeping enough or sleeping in excess is associated with increased morbidity and mortality. Yet, the convergent molecular mechanisms that link longevity and sleep are largely unknown. We performed a gene enrichment study that (1) identified genes associated with both longevity and sleep traits and (2) determined molecular pathways enriched among these shared genes. We manually curated two sets of genes, one associated with longevity and aging and the other with sleep traits (e.g., insomnia, narcolepsy, sleep duration, chronotype, among others), with both gene lists heavily driven by hits from recent large-scale Genome-Wide Association Studies. There were 47 overlapping genes between the gene list associated with sleep traits (1064 genes total) and the genes associated with longevity (367 genes total), indicating significantly more overlap than expected by chance. An overrepresentation analysis identified enriched pathways that suggest endocrine and epigenetic regulation as potential shared mechanisms between sleep traits and longevity. Concordantly, functional network analysis retrieved two clusters, being one associated with proteins of nuclear functions and the other, with extracellular proteins. This overlapping gene set, and the highlighted biological pathways may serve as preliminary findings for new functional investigations of sleep and longevity shared genetic mechanisms.

Trends in mortality from Alzheimer's disease in Brazil, 2000-2019.

OBJECTIVE: to analyze trends in mortality rates due to Alzheimer's disease in Brazil and its macro-regions by age and sex, from 2000 to 2019. METHODS: this was a time-series study on mortality from Alzheimer's disease in Brazil and its macro-regions by age and sex; data were obtained from the Mortality Information System; a Prais-Winsten model was used to analyze trends. RESULTS: there were 211,658 deaths in the period analyzed, with an increasing trend in Alzheimer's disease mortality in Brazil in elderly people aged 60-69 years (APC = 4.3; 95%CI 2.9;5.9), 70-79 years (APC = 8.1; 95%CI 4.8;11.5) and ≥ 80 years (APC = 11.3; 95%CI 8.1;14.6) and in all macro-regions, age groups and sexes. CONCLUSION: Brazil and all its macro-regions showed a rising trend in Alzheimer's disease mortality rates, following the global trend.

Genetic basis of sleep phenotypes and rare neurodevelopmental syndromes reveal shared molecular pathways.

Sleep-related phenotypes have been frequently reported in early on-set epileptic encephalopathies and in developmental delay syndromes, in particular in syndromes related to autism spectrum disorder. Yet the convergent pathogenetic mechanisms between these comorbidities are largely unknown. We first performed a gene enrichment study that identified shared risk genes among rare epileptic encephalopathies/neurodevelopmental disorders, rare developmental delay genetic syndromes and sleep disturbances. We then determined cellular and molecular pathways enriched among genes shared between sleep phenotypes and those two early onset mental illnesses, aiming to identify genetic disparities and commonalities among these phenotypic groups. The sleep gene set was observed as significantly overlapped with the two gene lists associated to rare genetic syndromes (i.e., epileptic encephalopathies/neurodevelopmental disorders and developmental delay gene sets), suggesting shared genetic contribution. Similarities across significantly enriched pathways between the two intersect lists comprehended mostly synapse-related pathways, such as retrograde endocannabinoid signaling, serotonergic, and GABAergic synapse. Network analysis indicates epileptic encephalopathies/neurodevelopmental disorders versus sleep-specific clusters and developmental delay versus sleep-specific clusters related to synaptic and transcriptional regulation, respectively. Longstanding functional patterns previously described in epileptic encephalopathies and neurodevelopmental disorders genetic architecture were recaptured after dissecting the overlap between the genes associated to those developmental phenotypes and sleep disturbances, suggesting that during neurodevelopment different molecular and functional mechanisms are related to alterations on circadian rhythm. The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between sleep disturbances and rare developmental syndromes.

Tendência de mortalidade por doença de Alzheimer no Brasil, 2000 a 2019 / Tendencias de mortalidad por enfermedad de Alzheimer en Brasil, 2000 a 2019 / Trends in mortality from Alzheimer's disease in Brazil, 2000-2019

Objetivo: analisar as tendências das taxas de mortalidade por doença de Alzheimer no Brasil e nas suas macrorregiões, por faixa etária e sexo, no período de 2000 a 2019. Métodos: estudo de séries temporais sobre mortalidade por doença de Alzheimer no Brasil e suas macrorregiões por faixa etária e sexo; os dados foram extraídos do Sistema de Informação sobre Mortalidade (SIM); o modelo de Prais-Winsten foi utilizado para análise das tendências. Resultados: houve 211.658 óbitos no período analisado, com tendência crescente na mortalidade por doença de Alzheimer no país em idosos de 60-69 anos (VPA = 4,3; IC95% 2,9;5,9), 70-79 anos (VPA = 8,1; IC95% 4,8;11,5) e ≥ 80 anos (VPA = 11,3; IC95% 8,1;14,6), e em todas as macrorregiões, faixas etárias e sexo. Conclusão: o Brasil e todas as suas macrorregiões apresentaram tendência crescente nas taxas de mortalidade por doença de Alzheimer, seguindo a tendência mundial.

Objective: to analyze trends in mortality rates due to Alzheimer's disease in Brazil and its macro-regions by age and sex, from 2000 to 2019. Methods: this was a time-series study on mortality from Alzheimer's disease in Brazil and its macro-regions by age and sex; data were obtained from the Mortality Information System; a Prais-Winsten model was used to analyze trends. Results: there were 211,658 deaths in the period analyzed, with an increasing trend in Alzheimer's disease mortality in Brazil in elderly people aged 60-69 years (APC = 4.3; 95%CI 2.9;5.9), 70-79 years (APC = 8.1; 95%CI 4.8;11.5) and ≥ 80 years (APC = 11.3; 95%CI 8.1;14.6) and in all macro-regions, age groups and sexes. Conclusion: Brazil and all its macro-regions showed a rising trend in Alzheimer's disease mortality rates, following the global trend.

Objetivo: analizar las tendencias en las tasas de mortalidad por enfermedad de Alzheimer en Brasil y sus macrorregiones por grupo de edad y sexo, de 2000 a 2019. Métodos: estudio de series temporales de mortalidad por enfermedad de Alzheimer en Brasil y sus macrorregiones por grupo de edad y sexo; los datos se obtuvieron del Sistema de Información sobre Mortalidad del Ministerio de Salud de Brasil; se utilizó el modelo Prais-Winsten para analizar tendencias. Resultados: hubo 211.658 óbitos, con tendencia creciente en la mortalidad por enfermedad de Alzheimer en el país, en adultos mayores de 60-69 años (VPA = 4,3; IC95% 2,9;5,9), 70-79 años (VPA = 8,1; IC95%: 4,8;11,5) y ≥ 80 años (VPA = 11,3; IC95% 8,1;14,6) y en todas las macrorregiones, grupos de edad y sexo. Conclusión: Brasil y todas sus macrorregiones mostraron una tendencia creciente en las tasas de mortalidad por enfermedad de Alzheimer siguiendo la tendencia mundial.