Identification of DNA Methylation Changes That Predict Onset of Post-traumatic Stress Disorder and Depression Following Physical Trauma

Ryznar

2023

Cells

Stress is associated with various epigenetic changes. Some stress-induced epigenetic changes are highly dynamic, whereas others are associated with lasting marks on the epigenome. In our study, a comprehensive narrative review of the literature was performed by investigating the epigenetic changes that occur with acute stress, chronic stress, early childhood stress, and traumatic stress exposures, along with examining those observed in post-mortem brains or blood samples of suicide completers and attempters. In addition, the transgenerational effects of these changes are reported. For all types of stress studies examined, the genes Nr3c1, OXTR, SLC6A4, and BDNF reproducibly showed epigenetic changes, with some modifications observed to be passed down to subsequent generations following stress exposures. The aforementioned genes are known to be involved in neuronal development and hormonal regulation and are all associated with susceptibility to mental health disorders including depression, anxiety, personality disorders, and PTSD (post-traumatic stress disorder). Further research is warranted in order to determine the scope of epigenetic actionable targets in individuals suffering from the long-lasting effects of stressful experiences.

Section: Traumatic Stressmentioning

confidence: 99%

Epigenetic Changes Associated with Different Types of Stressors and Suicide

Ryznar

2023

Cells

“…However, there was a strong association between clinical anxiety and PTPRN2 (rs3857647), which is required for noradrenaline, dopamine, and serotonin accumulation in the brain. Hypermethylated cytosine sites of PTPRN2 have been linked to depression in trauma survivors ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Genetics of psycho-emotional well-being: genome-wide association study and polygenic risk score analysis

Yakovchik,

Tolynyova,

Kashtanova

et al. 2024

Front. Psychiatry

BackgroundPsycho-emotional well-being is essential for living a life of satisfaction and fulfillment. However, depression and anxiety have become the leading mental health issues worldwide, according to the World Health Organization. Both disorders have been linked to stress and other psychological factors. Their genetic basis remains understudied.MethodsIn 2020–2021, the psycho-emotional well-being of 30,063 Russians with no known psychiatric history was assessed using the Hospital Anxiety and Depression Scale (HADS) for general mental health and the HADS subscale A (anxiety) for anxiety. Following the original instructions, an anxiety score of ≥11 points was used as the anxiety threshold. A genome-wide association study was performed to find associations between anxiety and HADS/HADS-A scores using linear and logistic regressions based on HADS/HADS-A scores as binary and continuous variables, respectively. In addition, the links between anxiety, sociodemographic factors (such as age, sex, and employment), lifestyle (such as physical activity, sleep duration, and smoking), and markers of caffeine and alcohol metabolism were analyzed. To assess the risk of anxiety, polygenic risk score modeling was carried out using open-access software and principal component analysis (PCA) to simplify the calculations (ROC AUC = 89.4 ± 2.2% on the test set).ResultsThere was a strong positive association between HADS/HADS-A scores and sociodemographic factors and lifestyle. New single-nucleotide polymorphisms (SNPs) with genome-wide significance were discovered, which had not been associated with anxiety or other stress-related conditions but were located in genes previously associated with bipolar disorder, schizophrenia, or emotional instability. The CACNA1C variant rs1205787230 was associated with clinical anxiety (a HADS-A score of ≥11 points). There was an association between anxiety levels (HADS-A scores) and genes involved in the activity of excitatory neurotransmitters: PTPRN2 (rs3857647), DLGAP4 (rs8114927), and STK24 (rs9517326).ConclusionOur results suggest that calcium channels and monoamine neurotransmitters, as well as SNPs in genes directly or indirectly affecting neurogenesis and synaptic functions, may be involved in the development of increased anxiety. The role of some non-genetic factors and the clinical significance of physiological markers such as lifestyle were also demonstrated.

“…Four out of eleven genes associated with methylation biomarkers have been reported as relevant in previous research. [10,[69][70][71][72][73][74][75][76] In previous studies, the altered methylation patterns of the INPP5A gene were associated with cognitive functions in both blood and the hippocampus samples. [69,70] The DIP2C gene has been previously reported to undergo changes in its methylation patterns in studies related to anxiety disorder, post-traumatic stress disorder (PTSD), and major depressive disorder.…”

Section: The Interpretation Of Eleven Genes Associated With 17 Methyl...mentioning

confidence: 90%

“…[69,70] The DIP2C gene has been previously reported to undergo changes in its methylation patterns in studies related to anxiety disorder, post-traumatic stress disorder (PTSD), and major depressive disorder. [10,[71][72][73][74] Furthermore, despite their distinct genomic positions, both INPP5A and DIP2C have been identified as markers in a blood-based study for diagnosing anxiety disorders. [75] The methylation and gene expression patterns of the ATP5F1A gene are known to be associated with Alzheimer's disease.…”

Section: The Interpretation Of Eleven Genes Associated With 17 Methyl...mentioning

confidence: 99%

Identification of 17 novel epigenetic biomarkers associated with anxiety disorders using differential methylation analysis followed by machine learning-based validation

Kwon,

Blazyte,

Jeon

et al. 2024

Preprint

Background: The changes in DNA methylation patterns may reflect both physical and mental well-being, the latter being a relatively unexplored avenue in terms of clinical utility for psychiatric disorders. In this study, our objective was to identify the methylation-based biomarkers for anxiety disorders and subsequently validate their reliability. Methods: A comparative differential methylation analysis was performed on whole blood samples from 94 anxiety disorder patients and 296 control samples using targeted bisulfite sequencing. Subsequent validation of identified biomarkers employed an artificial intelligence-based risk prediction models: a linear calculation-based methylation risk score model and two tree-based machine learning models: Random Forest and XGBoost. Results: 17 novel epigenetic methylation biomarkers were identified to be associated with anxiety disorders. These biomarkers were predominantly localized near CpG islands, and they were associated with two distinct biological processes: 1) cell apoptosis and mitochondrial dysfunction and 2) the regulation of neurosignaling. We further developed a robust diagnostic risk prediction system to classify anxiety disorders from healthy controls using the 17 biomarkers. Machine learning validation confirmed the robustness of our biomarker set, with XGBoost as the best-performing algorithm, an area under the curve of 0.876. Conclusion: Our findings support the potential of blood liquid biopsy in enhancing the clinical utility of anxiety disorder diagnostics. This unique set of epigenetic biomarkers holds the potential for early diagnosis, prediction of treatment efficacy, continuous monitoring, health screening, and the delivery of personalized therapeutic interventions for individuals affected by anxiety disorders.