Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression.

Genetic variants associated with major depressive disorder (MDD) are enriched in the regulatory genome. Here, we investigate gene-regulatory mechanisms underlying MDD compared to neurotypical controls by combining single-cell chromatin accessibility with gene expression in over 200,000 cells from the dorsolateral prefrontal cortex of 84 individuals. MDD-associated alterations in chromatin accessibility were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of NR4A2, an activity-dependent TF reactive to stress.

Behavioural, psychiatric, and cognitive phenotypes associated with numbers of repeats of the FRAXE allele on the FMR2 gene.

Background: The FRAXE site on the X-chromosome has a variable number of trinucleotide repeats. The rare condition Fragile XE has >200 repeats, but most X chromosomes have <60 such repeats, with evidence of a bimodal distribution. It is known that when the number of repeats is <60, the repeat number can increase from mother to son, which raises the question as to whether there is an evolutionary advantage in the increased size of these repeats.

Overweight/Obesity and Ancestral Environmental Smoking Exposures: A Summary of Results from the ALSPAC Cohort.

There is considerable discussion concerning the recent increase in the prevalence of overweight/obesity in children and adults. Although it is assumed that current diet and sedentary behavior are key contributors, these factors do not seem to be the only characteristics responsible. In this paper we summarize the findings we have obtained when assessing whether exposures in previous generations may have played a part in this change over time.

Strengthening Rigor and Reproducibility in Epigenome-Wide Association Studies of Social Exposures and Brain-Based Health Outcomes.

Purpose Of Review: Studies examining the effects of social factors on the epigenome have proliferated over the last two decades. Social epigenetics research to date has broadly demonstrated that social factors spanning childhood adversity, to neighborhood disadvantage, educational attainment, and economic instability are associated with alterations to DNA methylation that may have a functional impact on health. These relationships are particularly relevant to brain-based health outcomes such as psychiatric disorders, which are strongly influenced by social exposures and are also the leading cause of disability worldwide.

Epigenetic timing effects on child developmental outcomes: a longitudinal meta-regression of findings from the Pregnancy And Childhood Epigenetics Consortium.

Background: DNA methylation (DNAm) is a developmentally dynamic epigenetic process; yet, most epigenome-wide association studies (EWAS) have examined DNAm at only one timepoint or without systematic comparisons between timepoints. Thus, it is unclear whether DNAm alterations during certain developmental periods are more informative than others for health outcomes, how persistent epigenetic signals are across time, and whether epigenetic timing effects differ by outcome.

Methods: We applied longitudinal meta-regression models to published meta-analyses from the PACE consortium that examined DNAm at two timepoints-prospectively at birth and cross-sectionally in childhood-in relation to the same child outcome (ADHD symptoms, general psychopathology, sleep duration, BMI, asthma).

A blood- and brain-based EWAS of smoking.

DNA methylation offers an objective method to assess the impact of smoking. In this work, we conduct a Bayesian EWAS of smoking pack years (n = 17,865, ~850k sites, Illumina EPIC array) and extend it by analysing whole genome data of smokers and non-smokers from Generation Scotland (n = 46, ~4-21 million sites via TWIST and Oxford Nanopore sequencing). We develop mCigarette, an epigenetic biomarker of smoking, and test it in two British cohorts.

Blood-based DNA methylation markers for lung cancer prediction.

Objective: Screening high-risk individuals with low-dose CT reduces mortality from lung cancer, but many lung cancers occur in individuals who are not eligible for screening. Risk biomarkers may be useful to refine risk models and improve screening eligibility criteria. We evaluated if blood-based DNA methylation markers can improve a traditional lung cancer prediction model.

Blood-based epigenome-wide association study and prediction of alcohol consumption.

Alcohol consumption is an important risk factor for multiple diseases. It is typically assessed via self-report, which is open to measurement error through recall bias. Instead, molecular data such as blood-based DNA methylation (DNAm) could be used to derive a more objective measure of alcohol consumption by incorporating information from cytosine-phosphate-guanine (CpG) sites known to be linked to the trait.

Dietary inflammation and childhood adiposity: Analysis of individual participant data from six birth cohorts.

Background & Aims: Childhood adiposity and inflammation impact long-term health. However, associations between dietary inflammation and childhood adiposity are unclear. We investigated if more pro-inflammatory diets are associated with greater adiposity in early-, mid-, and late-childhood.

Maximizing insights from longitudinal epigenetic age data: simulations, applications, and practical guidance.

Background: Epigenetic age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk.

Characterising developmental dynamics of adult epigenetic clock sites.

Background: DNA methylation (DNAm), an epigenetic mechanism that regulates gene activity in response to genetic and environmental influences, changes as we age. DNAm at specific sites on the genome can be used to calculate 'epigenetic clocks', which are powerful biomarkers of age, as well as of ageing. However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life.

M2e nanovaccines supplemented with recombinant hemagglutinin protect chickens against heterologous HPAI H5N1 challenge.

Current poultry vaccines against influenza A viruses target the globular head region of the hemagglutinin (HA1), providing limited protection against antigenically divergent strains. Experimental subunit vaccines based on the conserved ectodomain of the matrix protein 2 (M2e) induce cross-reactive antibody responses, but fail to fully prevent virus shedding after low pathogenic avian influenza (LPAI) virus challenge, and are ineffective against highly pathogenic avian influenza (HPAI) viruses. This study assessed the benefits of combining nanoparticles bearing three tandem M2e repeats (NR-3M2e nanorings or NF-3M2e nanofilaments) with an HA1 subunit vaccine in protecting chickens against a heterologous HPAI H5N1 virus challenge.

Epigenetic Aging and Racialized, Economic, and Environmental Injustice: NIMHD Social Epigenomics Program.

Importance: Epigenetic age acceleration is associated with exposure to social and economic adversity and may increase the risk of premature morbidity and mortality. However, no studies have included measures of structural racism, and few have compared estimates within or across the first and second generation of epigenetic clocks.

Objective: To determine whether epigenetic age acceleration is positively associated with exposures to diverse measures of racialized, economic, and environmental injustice measured at different levels and time periods.

Maximizing Insights from Longitudinal Epigenetic Age Data: Simulations, Applications, and Practical Guidance.

Background: Epigenetic Age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk.

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.

Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation.

What makes clocks tick? Characterizing developmental dynamics of adult epigenetic clock sites.

DNA methylation (DNAm) at specific sites can be used to calculate 'epigenetic clocks', which in adulthood are used as indicators of age(). However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life. This knowledge could be used to optimize healthy aging well before the onset of age-related conditions.

Evaluation of a Combined Live Attenuated Vaccine against Lumpy Skin Disease, Contagious Bovine Pleuropneumonia and Rift Valley Fever.

The use of effective vaccines is among the most important strategies for the prevention and progressive control of transboundary infectious animal diseases. However, the use of vaccine is often impeded by the cost, a lack of cold chains and other factors. In resource-limited countries in Africa, one approach to improve coverage and reduce cost is to vaccinate against multiple diseases using combined vaccines.

Epigenetic aging & embodying injustice: US and .

Importance: Epigenetic accelerated aging is associated with exposure to social and economic adversity and may increase risk of premature morbidity and mortality. However, no studies have included measures of structural racism and few have compared estimates within or across the 1 and 2 generation of epigenetic clocks (the latter additionally trained on phenotypic data).

Objective: To determine if accelerated epigenetic aging is associated with exposures to diverse measures of racialized, economic, and environmental injustice measured at different levels and time periods.

An epigenome-wide analysis of DNA methylation, racialized and economic inequities, and air pollution.

Importance: DNA methylation (DNAm) provides a plausible mechanism by which adverse exposures become embodied and contribute to health inequities, due to its role in genome regulation and responsiveness to social and biophysical exposures tied to societal context. However, scant epigenome-wide association studies (EWAS) have included structural and lifecourse measures of exposure, especially in relation to structural discrimination.

Objective: Our study tests the hypothesis that DNAm is a mechanism by which racial discrimination, economic adversity, and air pollution become biologically embodied.

A history of asthma may be associated with grandparents' exposures to stress and cigarette smoking.

Within human epidemiological studies, associations have been demonstrated between grandparental exposures during childhood and grandchildren's outcomes. A few studies have assessed whether asthma has ancestral associations with exposure to cigarette smoking, but results have been mixed so far. In this study we used four generations: (F0 great-grandparents, F1 grandparents, F2 parents, F3 study children) of the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine whether there is evidence of associations between asthma in generations F2 or F3 and exposures to severe trauma in childhood and/or active cigarette smoking during the adolescence of grandmothers and grandfathers in generations F0 and F1 respectively, or of a history of a F0 or F1 grandmother smoking during pregnancy.

Fathers' preconception smoking and offspring DNA methylation.

Background: Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are, however, limited. We aim to identify epigenetic marks in offspring associated with father's preconception smoking.