Epigenomic profiling of young adults with mental health disorders in Northern Ireland

Abstract

Depression is a heterogeneous condition with complex underlying mechanisms, making it challenging to identify consistent genetic markers through genome-wide association studies (GWAS). The lack of robust results from GWAS highlights the need for exploring other molecular mechanisms, such as DNA methylation, to better understand the pathophysiology of depression and identify potential biomarkers. DNA methylation plays a key role in regulating various gene classes that can be altered by environmental exposures, consequently affecting key biological processes such as development, cellular function, and disease.

Among college students, high levels of mental health issues, self-harm, and suicidal behaviour are prevalent. Many students begin their college journey with pre-existing mental health conditions, which may be exacerbated during this period, while others develop new mental health issues. In young adults, epigenetic changes, including aberrant DNA methylation, may be associated with depression. This is also true for those with ADHD or those who have experienced childhood adversities, including physical or emotional ill-treatment, sexual abuse, or neglect. Childhood adversities are significant risk factors for developing psychiatric disorders such as Major Depressive Disorder (MDD), and Attention Deficit Hyperactivity Disorder (ADHD). Previous work investigating these issues was carried out as part of the Student Wellbeing Study (SWS) and Student Psychological Intervention Trial (SPIT), as part of the World Mental Health International College Student (WMH-ICS) initiative. The work carried out in this thesis aimed to explore adolescent mental health and look for associated biological markers, including DNA methylation changes. The epigenetic study analysed DNA methylation and involved a sub cohort of adolescents with depression (n=250) and healthy controls (n=250), matched by sex and age. Saliva samples were collected, DNA was extracted, and methylation was assessed using the Illumina EPIC array, processed with RnBeads, followed by gene ontology (GO) analysis using DAVID.

By employing genome-wide methylation analysis, the first study aimed to re-validate top hits from the Student Wellbeing Study and investigate the potential validation and control of transcription in cell line models. The second study examined methylation changes in a sub-cohort with comorbid depression and ADHD using GO analysis and bioinformatics tools such as DAVID, revealing an enrichment for neural genes. The overlap of biomarkers between the Abstract 16first and second studies was unique to depression only, with potential targets that could be validated in the larger catchment of study one.

In the third study, significant differential methylation levels were confirmed at several genomic sites linked to early childhood adversity, such as those involved in forebrain development, neurotransmission, and synaptogenesis. Gene ontology (GO) analysis revealed FDR-significant enrichment for neurological and developmental pathways, suggesting that changes in these neurobiological pathways could underpin the biological mechanisms affected by childhood adversities. Additionally, a potential methylation quantitative trait locus (meQTL) associated with the inflammatory response was investigated named TGFBR3. This gene plays a key role in regulating immune and inflammatory processes, which are implicated in various psychiatric conditions, including depression. This meQTL, specifically the genotype G/G, was prevalent in young adults exposed to multiple childhood adversities.

Overall, this thesis confirms and extends previous observations of an altered methylome in inflammatory and immune-related genes in young adults with depression. Notably, this is the first study to investigate methylation in young adults with depression in Ireland, considering comorbidities such as ADHD and adverse childhood experiences. The results focus on a particular and at-risk group, revealing the link between inflammation, epigenetic changes, and mental health.

Thesis is embargoed until 31st May 2027

Date of Award	Mar 2025
Original language	English
Supervisor	Rachelle Irwin (Supervisor), Siobhan O'Neill (Supervisor), Elaine Murray (Supervisor) & Dominic Mc Sherry (Supervisor)