Psychiatric disorders such as major depressive disorder, bipolar disorder and schizophrenia are a tremendous burden on society, globally accounting for more than 30% of years lived with a disability and more than 10% of disability-adjusted life-years. Although there is a global effort to prevent the aetiology and progression of these disorders, we still know very little about the biological mechanisms that are responsible for their onset. This is partly due to the complexity of these disorders, with genetic factors and environmental factors both conferring a degree of influence. Nevertheless, due to studies showing strong associations between these disorders and certain environmental factors, as well as advancements in large-scale collaborative genetic studies and molecular biology tools, we are now better able to understand the aetiology of these disorders and find better ways of treating them. This PhD seeks to explore the role of three biological mechanisms in relation to psychiatric disorder aetiology and/or drug treatment: inflammation, telomere length and hippocampal neurogenesis. Inflammatory markers are reported to be higher amongst major depressive disorder patients (e.g. C-reactive protein and interleukin-6). The first two data chapters within this PhD aim to tease apart the causes of heightened inflammation in major depressive disorder, using childhood maltreatment data and polygenic epidemiology. This work reveals the potential importance of body mass index in driving heighted inflammation amongst major depressive disorder patients. Telomere length is marker of cell age and is generally shorter (indicative of faster ageing) amongst those at risk for age-related disease and amongst psychiatric disorder patients. In the third and fourth data chapters, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. Our work revealed that polygenic risk for psychiatric disorders does not predict shorter telomere length in a UK population sample, implicating the importance of environmental factors in driving shorter telomere length amongst patients. Nevertheless, using linkage disequilibrium score regression our work confirmed that telomere length is a polygenic trait, and we identify the first polygenic risk score capable of explaining over 4% of the variance in telomere length. We confirm that chronic lithium use is associated with longer telomere length amongst bipolar disorder patients, suggesting that lithium may have anti-ageing properties, but we found this effect to be moderated by inter-individual genetic variation related to telomere length. Adult hippocampal neurogenesis describes the birth of new neurons in the adult hippocampus. It is a cellular mechanism that reduces with age and is hypothesized to be inhibited amongst psychiatric disorder patients and reversed with treatment. In this final chapter, we attempt to better understand lithium’s telomere-lengthening and neurogenic mechanism of action by studying its effects using an in vitro human hippocampal ageing model. We show that hippocampal cell ageing is associated with cellular senescence, although long-term lithium exposure can promote hippocampal cell differentiation.
|Date of Award||31 Jan 2020|
|Supervisor||Timothy Powell (Supervisor) & Sandrine Thuret (Supervisor)|