AbstractPsychiatric disorders are among the leading health concerns worldwide, with one in four people being affected by a mental health problem at some point in their life. While the economic burden has been on the rise, progress in treatments have remained stagnant due to the complexity of such disorders. To gain a better understanding in the aetiology of psychiatric disorders, in this thesis, I investigated the relation of environmental factors, genetic variation and methylation with brain structure/function and reinforcement-related behaviour and psychopathology. This work aims at (i) characterising mechanisms by which environmental influences, including psychosocial stress exert their effects on behaviour, (ii) identifying epigenetics/genetic markers related to behaviour and development of psychopathology, and (iii) examine how brain structure/function could relate the underlying biological mechanisms associated with behavioural outcomes.
In the first half of this thesis, I examined the effects of DNA methylation in the longitudinal IMAGEN imaging – genetics cohort of 2000 adolescents and related them to measures of psychopathology relevant for different psychiatric disorders, including substance use. In two separate epigenome-wide studies, novel biological mechanisms underlying substance use wereidentified: allele-specific differential methylation of SPDEF (Chapter 3) and longitudinal differential methylation of roughly 11,000 genes (Chapter 4) were found to be associated with adolescent alcohol consumption respectively. In both studies, changes to the brain were also
found to be involved in the gene-behaviour relationship. The second half of this thesis, I investigated the translational aspects of biological mechanisms underlying behaviour and psychopathology. In collaboration with other research groups, I replicated novel findings of alcohol-associated DLGAP2 methylation in post-mortem brain tissues (Chapter 5) and alcohol-related effects of SMPD3 in mice (Chapter 6), in normal human populations drawn from both the IMAGEN cohort and UK Biobank respectively. With virtually no progress in development of novel treatments over the last couple of decades and a constant increase in burden of psychiatric diseases, it is pertinent that psychiatric research aims at improving psychiatric nosology and discerning psychiatric pathology.
Overall, this thesis contributes to existing literature and highlights the importance of multimodal approaches into better understanding the complex biological underpinnings of psychiatric disorders such as substance use.
|Date of Award||1 Jan 2020|
|Supervisor||Cathryn Lewis (Supervisor) & Gunter Schumann (Supervisor)|