Alcohol Use Disorder-Associated DNA Methylation in the Nucleus Accumbens and Dorsolateral Prefrontal Cortex.

Background: Alcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms that underlie the development and progression of AUD remains limited. Here, we investigated AUD-associated DNA methylation changes within and across 2 addiction-relevant brain regions, the nucleus accumbens and dorsolateral prefrontal cortex.

A Perspective on Evaluating Life Stage Differences in Drug Dosages for Drug Labeling and Instructions.

Drug labeling and instructions provide essential information for patients regarding the usage of drugs. Instructions for the dosage of drug usage are critical for the effectiveness of the drug and the safety of patients. The dosage of many drugs varies depending on the patient's age.

Investigating neonatal health risk variables through cell-type specific methylome-wide association studies.

Adverse neonatal outcomes are a prevailing risk factor for both short- and long-term mortality and morbidity in infants. Given the importance of these outcomes, refining their assessment is paramount for improving prevention and care. Here we aim to enhance the assessment of these often correlated and multifaceted neonatal outcomes.

Alcohol Use Disorder-Associated DNA Methylation in the Nucleus Accumbens and Dorsolateral Prefrontal Cortex.

Background: Alcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms underlying the development and progression of AUD remain limited. Here, we interrogate AUD-associated DNA methylation (DNAm) changes within and across addiction-relevant brain regions: the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC).

The Impact of Childhood Mental Health and Substance Use on Methylation Aging Into Adulthood.

Objective: To test whether childhood mental health symptoms, substance use, and early adversity accelerate the rate of DNA methylation (DNAm) aging from adolescence to adulthood.

Method: DNAm was assayed from blood samples in 381 participants in both adolescence (mean [SD] age = 13.9 [1.

Fine-grained cell-type specific association studies with human bulk brain data using a large single-nucleus RNA sequencing based reference panel.

Brain disorders are leading causes of disability worldwide. Gene expression studies provide promising opportunities to better understand their etiology but it is critical that expression is studied on a cell-type level. Cell-type specific association studies can be performed with bulk expression data using statistical methods that capitalize on cell-type proportions estimated with the help of a reference panel.

Methylome-wide association study of anxiety disorders.

Anxiety Disorders (ANX) such as panic disorder, generalized anxiety disorder, and phobias, are highly prevalent conditions that are moderately heritable. Evidence suggests that DNA methylation may play a role, as it is involved in critical adaptations to changing environments. Applying an enrichment-based sequencing approach covering nearly 28 million autosomal CpG sites, we conducted a methylome-wide association study (MWAS) of lifetime ANX in 1132 participants (618 cases/514 controls) from the Netherlands Study of Depression and Anxiety.

Genes implicated by a methylome-wide schizophrenia study in neonatal blood show differential expression in adult brain samples.

Schizophrenia is a disabling disorder involving genetic predisposition in combination with environmental influences that likely act via dynamic alterations of the epigenome and the transcriptome but its detailed pathophysiology is largely unknown. We performed cell-type specific methylome-wide association study of neonatal blood (N = 333) from individuals who later in life developed schizophrenia and controls. Suggestively significant associations (P < 1.

A method to improve the reproducibility of findings from epigenome- and transcriptome-wide association studies.

Reproducibility is a cornerstone of scientific progress. In epigenome- and transcriptome-wide association studies (E/TWAS) failure to reproduce may be the result of false discoveries. Whereas multiple methods exist to control false discoveries due to sampling error, minimizing false discoveries due to outliers and other data artefacts remains challenging.

A single-nucleus transcriptomics study of alcohol use disorder in the nucleus accumbens.

Gene expression studies offer promising opportunities to better understand the processes underlying alcohol use disorder (AUD). As cell types differ in their function, gene expression profiles will typically vary across cell types. When studying bulk tissue, failure to account for this cellular diversity has a detrimental impact on the ability to detect disease associations.

DNA methylation signatures of childhood trauma predict psychiatric disorders and other adverse outcomes 17 years after exposure.

Childhood trauma is robustly linked to a broad range of adverse outcomes with consequences persisting far into adulthood. We conducted a prospective longitudinal study to predict psychiatric disorders and other adverse outcomes from trauma-related methylation changes 16.9 years after trauma exposure in childhood.

Transcriptome-wide association study for postpartum depression implicates altered B-cell activation and insulin resistance.

Postpartum depression (PPD) affects 1 in 7 women and has negative mental health consequences for both mother and child. However, the precise biological mechanisms behind the disorder are unknown. Therefore, we performed the largest transcriptome-wide association study (TWAS) for PPD (482 cases, 859 controls) to date using RNA-sequencing in whole blood and deconvoluted cell types.

Early adversities accelerate epigenetic aging into adulthood: a 10-year, within-subject analysis.

Background: Longitudinal studies are needed to clarify whether early adversities are associated with advanced methylation age or if they actually accelerate methylation aging. This study test whether different dimensions of childhood adversity accelerate biological aging from childhood to adulthood, and, if so, via which mechanisms.

Methods: 381 participants provided one blood sample in childhood (average age 15.

Dual methylation and hydroxymethylation study of alcohol use disorder.

Using an integrative, multi-tissue design, we sought to characterize methylation and hydroxymethylation changes in blood and brain associated with alcohol use disorder (AUD). First, we used epigenomic deconvolution to perform cell-type-specific methylome-wide association studies within subpopulations of granulocytes/T-cells/B-cells/monocytes in 1132 blood samples. Blood findings were then examined for overlap with AUD-related associations with methylation and hydroxymethylation in 50 human post-mortem brain samples.

DNA methylation of the KLK8 gene in depression symptomatology.

Background: Depression is a common, complex, and debilitating mental disorder estimated to be under-diagnosed and insufficiently treated in society. Liability to depression is influenced by both genetic and environmental risk factors, which are both capable of impacting DNA methylation (DNAm). Accordingly, numerous studies have researched for DNAm signatures of this disorder.

A targeted solution for estimating the cell-type composition of bulk samples.

Background: To avoid false-positive findings and detect cell-type specific associations in methylation and transcription investigations with bulk samples, it is critical to know the proportions of the major cell-types.

Results: We present a novel approach that allows for precise estimation of cell-type proportions using only a few highly informative methylation markers. The most reliable estimates were obtained with 17 amplicons (34 CpGs) using the MuSiC estimator, for which the average correlations between the estimated and the true cell-type proportions were 0.

A methylation study implicates the rewiring of brain neural circuits during puberty in the emergence of sex differences in depression symptoms.

Background: Women are 1.5-3 times more likely to suffer from depression than men. This sex bias first emerges during puberty and then persists across the reproductive years.

Methylomic Investigation of Problematic Adolescent Cannabis Use and Its Negative Mental Health Consequences.

Objective: The impact of adolescent cannabis use is a pressing public health question owing to the high rates of use and links to negative outcomes. This study considered the association between problematic adolescent cannabis use and methylation.

Method: Using an enrichment-based sequencing approach, a methylome-wide association study (MWAS) was performed of problematic adolescent cannabis use in 703 adolescent samples from the Great Smoky Mountain Study.

An integrative study of five biological clocks in somatic and mental health.

Biological clocks have been developed at different molecular levels and were found to be more advanced in the presence of somatic illness and mental disorders. However, it is unclear whether different biological clocks reflect similar aging processes and determinants. In ~3000 subjects, we examined whether five biological clocks (telomere length, epigenetic, transcriptomic, proteomic, and metabolomic clocks) were interrelated and associated to somatic and mental health determinants.

Test-statistic inflation in methylome-wide association studies.

Recent years have seen a surge of methylome-wide association studies (MWAS). We observed that many of these studies suffer from test statistic inflation that is most likely caused by commonly used quality control (QC) pipelines not going far enough to remove technical artefacts. To support this claim, we reanalysed GEO datasets with an improved QC pipeline that reduced test-statistic inflation parameter lambda from the original mean/median of 20.

Cell Type-Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder.

Background: We sought to characterize methylation changes in brain and blood associated with major depressive disorder (MDD). As analyses of bulk tissue may obscure association signals and hamper the biological interpretation of findings, these changes were studied on a cell type-specific level.

Methods: In 3 collections of human postmortem brain (n = 206) and 1 collection of blood samples (N = 1132) of MDD cases and controls, we used epigenomic deconvolution to perform cell type-specific methylome-wide association studies within subpopulations of neurons/glia for the brain data and granulocytes/T cells/B cells/monocytes for the blood data.