Exploring epigenetic drift and rare epivariations in amyotrophic lateral sclerosis by epigenome-wide association study.

During the last decades, our knowledge about the genetic architecture of sporadic amyotrophic lateral sclerosis (sALS) has significantly increased. However, besides the recognized genetic risk factors, also the environment is supposed to have a role in disease pathogenesis. Epigenetic modifications reflect the results of the interaction between environmental factors and genes and may play a role in the development and progression of ALS. A recent epigenome-wide association study (EWAS) in blood identified differentially methylated positions mapping to 42 genes involved in cholesterol biosynthesis and immune-related pathways. Here we performed a genome-wide DNA methylation analysis in the blood of an Italian cohort of 61 sALS patients and 61 healthy controls. Initially, a conventional genome-wide association analysis was performed, and results were subsequently integrated with the findings from the previous EWAS using a meta-analytical approach. To delve deeper into the significant outcomes, over-representation analysis (ORA) was employed. Moreover, the epigenetic signature obtained from the meta-analysis was examined to determine potential associations with chemical compounds, utilizing the Toxicogenomic Database. Expanding the scope of the epigenetic analysis, we explored both epigenetic drift and rare epivariations. Notably, we observed an elevated epigenetic drift in sALS patients compared to controls, both at a global and single gene level. Interestingly, epigenetic drift at a single gene level revealed an enrichment of genes related to the neurotrophin signaling pathway. Moreover, for the first time, we identified rare epivariations exclusively enriched in sALS cases associated with 153 genes, 88 of whom with a strong expression in cerebral areas. Overall, our study reinforces the evidence that epigenetics may contribute to the pathogenesis of ALS and that epigenetic drift may be a useful diagnostic marker. Moreover, this study suggests the potential role of epivariations in ALS.

Epigenetics of Autism Spectrum Disorders: A Multi-level Analysis Combining Epi-signature, Age Acceleration, Epigenetic Drift and Rare Epivariations Using Public Datasets.

BACKGROUND: Epigenetics of Autism Spectrum Disorders (ASD) is still an understudied field. The majority of the studies on the topic used an approach based on mere classification of cases and controls. OBJECTIVE: The present study aimed at providing a multi-level approach in which different types of epigenetic analysis (epigenetic drift, age acceleration) are combined. METHODS: We used publicly available datasets from blood (n = 3) and brain tissues (n = 3), separately. Firstly, we evaluated for each dataset and meta-analyzed the differential methylation profile between cases and controls. Secondly, we analyzed age acceleration, epigenetic drift and rare epigenetic variations. RESULTS: We observed a significant epi-signature of ASD in blood but not in brain specimens. We did not observe significant age acceleration in ASD, while epigenetic drift was significantly higher compared to controls. We reported the presence of significant rare epigenetic variations in 41 genes, 35 of which were never associated with ASD. Almost all genes were involved in pathways linked to ASD etiopathogenesis (i.e., neuronal development, mitochondrial metabolism, lipid biosynthesis and antigen presentation). CONCLUSION: Our data support the hypothesis of the use of blood epi-signature as a potential tool for diagnosis and prognosis of ASD. The presence of an enhanced epigenetic drift, especially in brain, which is linked to cellular replication, may suggest that alteration in epigenetics may occur at a very early developmental stage (i.e., fetal) when neuronal replication is still high.

Role of epigenetics in the clinical evolution of COVID-19 disease. Epigenome-wide association study identifies markers of severe outcome.

BACKGROUND: COVID-19 has a wide spectrum of clinical manifestations and given its impact on morbidity and mortality, there is an unmet medical need to discover endogenous cellular and molecular biomarkers that predict the expected clinical course of the disease. Recently, epigenetics and especially DNA methylation have been pointed out as a promising tool for outcome prediction in several diseases. METHODS AND RESULTS: Using the Illumina Infinium Methylation EPIC BeadChip850K, we investigated genome-wide differences in DNA methylation in an Italian Cohort of patients with comorbidities and compared severe (n = 64) and mild (123) prognosis. Results showed that the epigenetic signature, already present at the time of Hospital admission, can significantly predict risk of severe outcomes. Further analyses provided evidence of an association between age acceleration and a severe prognosis after COVID-19 infection. The burden of Stochastic Epigenetic Mutation (SEMs) has been significantly increased in patients with poor prognosis. Results have been replicated in silico considering COVID-19 negative subjects and available previously published datasets. CONCLUSIONS: Using original methylation data and taking advantage of already published datasets, we confirmed in the blood that epigenetics is actively involved in immune response after COVID-19 infection, allowing the identification of a specific signature able to discriminate the disease evolution. Furthermore, the study showed that epigenetic drift and age acceleration are associated with severe prognosis. All these findings prove that host epigenetics undergoes notable and specific rearrangements to respond to COVID-19 infection which can be used for a personalized, timely, and targeted management of COVID-19 patients during the first stages of hospitalization.

Autism Spectrum Disorder and collective catering service: results of the pilot study FOOD-AUT.

Objective: Individuals with Autism Spectrum Disorder (ASD) often exhibit a low dietary diversity due to food selectivity that leads them to a marked preference for high-energy-density food, exposing them to risk of malnutrition. Despite these aspects, specific recommendations and targeted menus for this population are missing. The pilot study FOOD-AUT addresses this issue by developing canteen menus meeting the nutritional and sensory needs of adults with ASD, aiming to reduce their food selectivity, and consequently improving their health. Methods: The project, funded by Gruppo Pellegrini S.p.A, was conducted at the daycare service of Sacra Famiglia Onlus Foundation, between March-2022 to March-2023. The study was divided into two phases. Observational phase: a comparison was made between the enrolled subjects' nutritional needs and the nutrient content of the administered menus during the daycare service. Then mealtime compliance was assessed using standardized meal evaluation forms, both quantitative and qualitative. Intervention phase: canteen menus targeted to the individuals' nutritional and sensory needs were administered and their acceptability was evaluated. Results: Twenty-two individuals with ASD, aged 19-48, 72.7% males, were enrolled. Overweight and obesity prevalence were 54.5 and 18.2%, respectively. The observational phase showed how the most accepted foods had specific sensorial characteristics in line with the scientific literature. Adapting the menus improved food acceptance and reduced food waste. Conclusion: The results highlighted the need for adapted menus and greater attention to the way meals are delivered and consumed to improve nutritional status and therefore health of this population at increased risk of malnutrition. Clinical trial registration: ClinicalTrial.gov, unique identifier: NCT05978895.