Environmental, genetic and epigenetic contributors to the risk of bipolar disorder

Bipolar disorder (BD) is a complex mental illness for which both environmental and biological (genetic and epigenetic) factors play an aetiological role. This thesis aimed to find factors behind risk of psychopathology, using a multi-site cohort with parents or siblings with BD (high-risk; HR) and offspring of healthy control parents. My aim was to explore the trajectory towards development of BD and related psychopathology, guided by the hypothesis that DNA methylation (DNAm), a key epigenetic process, may provide a molecular link of relevant gene-environment interactions. Firstly, association of stressful life events and family environment with clinical status was investigated. Next, blood-derived DNAm of a subset with available genotype data (n=415) was used to investigate epigenetic signals. Epigenome-wide association studies were used to identify differentially methylated CpG sites based on familial risk and emergent clinical status, and polygenic risk. Finally, methylation-derived markers, indexing C-reactive protein (CRPm) and neutrophil-to-lymphocyte ratio (NLRm), were used to investigate the influence of inflammatory processes in the development of psychopathology. Stressful life events and an unbalanced family environment increase risk of emergent psychopathology, providing targets for early intervention. Nominally differentially methylated CpG sites that were related to family history, clinical transition and polygenic risk showed enrichment in neurological pathways and functions. Family environment influenced DNAm signatures of clinical transition, and methylation profile scores showed partial prediction of clinical transition in independent validation. The influence of polygenic risk scores for BD revealed wide-ranging nominal effects on DNAm signatures and an epigenome-wide significant signal at mitochondrial gene VARS2, within the major histocompatibility complex (MHC) region. The relationship between DNAm signatures and polygenic background was independently validated. While the role of inflammation on psychopathology was not strong, CRPm could potentially predict psychopathology in HR individuals, and a trend of higher NLRm and CRPm was evident in HR with suicidal ideation. My findings showed that epigenetic processes are impacted by both familial background and genetic predisposition, may reflect underlying environmental exposures, and influence emergent psychopathology, providing insights into biological dysregulation leading to BD