Investigating The Genetic and Epigenetic Interplay in Mental Health
We spoke to Dr. Stéphanie Le Hellard about their project which aims to untangle the roles of genetics, epigenetics, and gene expression in mental disorder development, particularly focusing on DNA methylation. Their research may contribute to the development of personalized treatment approaches in psychiatry.
Psychiatric disorders significantly contribute to human suffering and morbidity. Their prevalence has been on the rise and however, their causes are still not fully understood. Psychiatric disorders differ in symptomatology but share a complex multifactorial etiology rooted in the interplay of genetic, and environmental factors. Genetic and environmental factors can modify gene expression, acting like switches that can turn genes “on and off”. These alterations, known as epigenetic changes, occur through various mechanisms. One such mechanism is DNA methylation. Here, an extra chemical component gets attached to the DNA molecule, leaving the genetic code unchanged but still influencing gene activity. Recent research highlights the role of these epigenetic changes in the development and outcome of severe mental disorders.
To enhance the quality of life for patients, and improve early diagnosis, treatment, and prevention, a deeper understanding of the biology of these conditions is essential. Dr. Stephanie Le Hellard talks about the project “DNA methylation in psychiatric disorders, and mediation of gene by environment effects, from birth to adulthood” which aims to explore novel perspectives on genetic and environmental contributions by investigating the epigenetics of four psychiatric conditions: schizophrenia, obsessive-compulsive disorder, bipolar disorder, and attention deficit hyperactivity disorder. Their research focuses on understanding how epigenetic modifications, specifically DNA methylation, may play a role in these disorders and how environmental factors can influence these modifications. The team also examines the impact of well known environmental risk factors on DNA methylation, e.g. childhood trauma, birth complications, and cannabis use on DNA methylation, which may reveal potential molecular effect of these risk factors in psychiatric conditions.
Collaborating with the Norwegian Center for Mental Health Research (NORMENT) and the Bergen Centre for Brain Plasticity (BCBP), in partnership with leading national and international research groups, this project uses data from various sources. By uniting scientific communities through collaborations with NORMENT, BCBP, the Norwegian
risk factors for schizophrenia
Mother-Child Cohort, and the consortium on persistent ADHD, this research offers a unique opportunity for insights into the methylation patterns associated with psychiatric disorders. This project will potentially lead to advances in psychiatric disorder diagnosis, prevention, and therapy. The project draws upon diverse expertise in statistical and functional genetics, with insights from clinical research.
Gender-Specific Epigenetic Signatures in Schizophrenia
Schizophrenia is a severe psychiatric disorder that shows differences between genders in age of onset and risk of negative versus affective symptoms. The molecular mechanisms behind sex differences in schizophrenia’s epidemiology and clinical features are not yet understood. In order to address this gap, the team conducted sex-stratified meta-analyses of epigenome-wide association studies (EWAS) for schizophrenia.
“By using a method called epigenome-wide association studies, we can scan the entire genome for methylation variations. This helps us see if certain traits, like schizophrenia, are linked to specific methylation changes. In our research, we compared patients with schizophrenia and controls to identify DNA methylation differences. We’ve identified several regions of the genome where the DNA methylation is different between cases and controls. Interestingly, these effects are different between males and females, showing more pronounced
effects in females than males. DNA methylation is a biological marker, affected by factors like sex hormones and age. These findings hint that in schizophrenia, the DNA methylation effects are different between males and females.” explains Dr. Le Hellard.
This gender-specific discovery helps research understand how biological markers vary between sexes and might influence the disorder’s development. The differences in DNA methylation pathways between males and females might indicate that distinct biological processes underlie schizophrenia.
The researchers also discovered new positions in the DNA where methylation changes occur in those affected by schizophrenia. These changes often relate to genes involved in brain function, immune responses, and energy regulation. Some genes, like COMT and KCNAB3, may even serve as potential drug targets for treating schizophrenia. These findings mark a significant step toward understanding how gender-specific DNA alterations could lead to improved diagnostics and personalized treatments for schizophrenia.
Examining Childhood Trauma’s Impact Through DNA Methylation
The researchers examined how childhood trauma might influence severe mental illnesses through DNA methylation changes. They investigated 602 patients with severe mental disorders using a blood-based epigenome-wide association
study, focusing on five types of trauma and the overall trauma score. A high majority (83.2%) of patients who suffer from psychiatric disorders, reported experiencing childhood trauma, with emotional neglect being the most common subtype. The team discovered one specific DNA methylation change linked to the gene TANGO6 concerning physical neglect. Additionally, they found 17 different DNA regions showing altered methylation associated with different trauma types. Many of these regions were linked to genes previously associated with conditions like post-traumatic stress disorder (PTSD) and cognitive impairments.
“We wanted to see if there were any lasting effects of this trauma visible in adults, especially in patients. Surprisingly, we found certain positions in the DNA where individuals who reported childhood trauma had different methylation patterns. What made this discovery even more interesting was that these affected genes were also linked to PTSD.” says Dr. Le Hellard. The team is now coordinating an effort for a meta-analysis of EWAS from several centres in order to identify more DNA methylation variations associated with childhood trauma.
DNA Methylation and Birth Asphyxia
In another study, the researchers explored how birth asphyxia, a condition affecting oxygen delivery to the brain during birth, might relate to later psychiatric diagnoses. Their study involved 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls, using data from the Medical Birth Registry of Norway. They found a connection between DNA methylation changes and exposure to birth asphyxia. This interaction differed between healthy individuals and patients. In healthy controls, birth asphyxia was associated with increased methylation, while in patients with schizophrenia or bipolar disorder, it was linked to decreased methylation. These changes were observed in specific DNA regions crucial for brain development and function. These regions of DNA were linked to various essential processes in the brain, such as oligodendrocyte survival, brain maturation, neural plasticity, and axonal transport.
“We explored the impact of birth asphyxia on schizophrenia, considering that individuals with schizophrenia often have a higher risk of experiencing this condition at birth. We aimed to uncover if these individuals showed any lasting effects on DNA methylation due to birth asphyxia. Surprisingly, we identified specific regions in their DNA where those who had experienced birth asphyxia showed distinct methylation patterns even in adulthood. This imprinting effect suggests that the impact of
birth asphyxia can leave a lasting mark on an individual’s DNA, potentially influencing their health later in life.” explains Dr. Le Hellard.
The effects of pharmaceutical and cognitive treatment on DNA methylation
In addition to using DNA methylation to understand the molecular mechanisms of mental disorders, Le Hellard et al. focus on the potential of these methods to identify molecular mechanisms associated with treatment and response to treatment of mental disorders.
These studies also have the potential to identify predictive changes that signal which patients could benefit from specific treatments.
The researchers are studying DNA methylation changes that are associated with the use of antipsychotic medications. For instance, in one study, they compared individuals who are under antipsychotic treatment with a healthy cohort from the Norwegian population.
Currently, they are collaborating with Brazilian researchers, examining DNA methylation changes in patients undergoing Risperidone treatment over a longer period.
In collaboration with Leif Oltedal and Ute Kessler at Haukeland University Hospital, the researchers are exploring DNA methylation changes before and after electroconvulsive therapy. Their objective is to pinpoint genes affected by this treatment and identify differences in DNA methylation between treatment-responsive patients and non-responders. The researchers hope their findings will be able to contribute to predicting which patients will benefit from electroconvulsive therapy.
In collaboration with the Bergen Center for Brain Plasticity, the researchers are investigating DNA methylation in patients undergoing concentrated exposure therapy for obsessive complulsive disorder disorder. In this study, they are comparing DNA methylation in patients who are receiving treatment for OCD with their treatment response.
Understanding alterations in DNA methylation offers valuable insights into the intricate interplay among genetics, the environment, and mental disorders. These epigenetic changes could serve as markers, illuminating how environmental and behavioral changes, like stopping cannabis use, could affect our genes. They can offer insight into treatment-related changes even before the initiation of treatment. The team’s current endeavors are focused on projects that aim to pinpoint epigenetic changes capable of predicting treatment responses. This initiative aims to pave the way for personalized treatment approaches in mental health.
DNA METHyLATIoN IN PSyCHIATrIC DISorDErS
DNA methylation in psychiatric disorders, and mediation of gene by environment effects, from birth to adulthood
Project objectives
The project “DNA methylation in psychiatric disorders, and mediation of gene by environment effects, from birth to adulthood” delves into the intricate interplay of genetics, epigenetics, and gene expression in psychiatric disorders, with a focus on DNA methylation. The research aims to unravel novel insights that could potentially lead to personalized treatment approaches in mental health.
Project Funding
This project is funded by the Research Council of Norway (grant numbers 223273, 273446 and 250299).
Project Partners
Dr Tetyana Zayats, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Contact Details
Project Coordinator, Professor Stéphanie Le Hellard Professor in Human Genetics, PhD Epigenetics of Mental Disorders, Department of Clinical Sciences University of Bergen N-5020 Bergen, Norway.
T: +47 900 58 089
E: Stephanie.LeHellard@uib.no W: https://www.uib.no/en/persons/Stephanie. Francoise.Claire.Le.Hellard#uib-tabs-research
https://www.researchsquare.com/article/rs-3427549/v1 https://pubmed.ncbi.nlm.nih.gov/35501310/ https://www.nature.com/articles/s41398-023-02709-7 https://pubmed.ncbi.nlm.nih.gov/37904091/ https://www.sciencedirect.com/science/article/abs/pii/ S0924977X23002560
Stéphanie Le Hellard is a Professor of Human Genetics at the Department of Clinical Science at The University of Bergen in Norway. Her research is focused on identifying the impact of genetics, epigenetics, and gene expression in the development of mental disorders.
