A multi-omic approach to investigating biological mechanisms related to the aetiology and treatment of major depressive disorder.

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Major depression is a brain disorder that affects 350 million people worldwide. Depressed patients experience extreme periods of low mood, loss of pleasure, problems with their appetite and difficulties sleeping. Currently, antidepressants are the first line of treatment for depression but only one third of patients respond to the first prescribed antidepressant, and one third will not respond to multiple forms of treatment. Consequently, a better understanding of what causes major depression and what affects response to antidepressants is desperately needed.At least three biological mechanisms have been proposed to be important for causing major depression. Firstly, depressed patients tend to have shorter telomeres in their blood cells than non-depressed subjects. Telomeres are stretches of DNA at the end of each chromosome that shorten in length with our normal aging. It has been hypothesized that depressed patients have some cells which demonstrate advanced 'cellular aging' and die more readily. This could have subsequent impacts on the viability of neuronal cells and brain function.Secondly, depressed patients have higher levels of a protein called interleukin-6 in their blood. Interleukin-6 is classically involved in inflammation, but recent research suggests it interferes with brain communication and function. Thirdly, depression has been linked with abnormal function in the hippocampus, a structure in the brain which is important in regulating memory and mood. Throughout our lifetime stem cells in the hippocampus grow and generate new neurons in a continuous manner. However, it has been suggested that there is a reduction in the generation of these new neurons in depressed cases, based on evidence from animal models. Complementing this theory, antidepressants stimulate the generation of new neurons in the hippocampus. However, it remains unknown whether this is the true mechanism behind antidepressant action.Using new statistical techniques on large clinical genetic datasets we aim to test whether each of our three biological mechanisms are really causal to major depression, or whether they instead, represent an effect of having the disease. Broadly, we will achieve this using a three-step plan. Firstly, we will investigate which genes are involved in each mechanism (e.g. which genes affect telomere length). Secondly, we will combine the most significant genes affecting each mechanism into a single genetic signature. Thirdly, we will test whether genetic signatures for each mechanism predict an increased risk of major depression. A genetic signature associated with a mechanism, which additionally predicts major depression, would support the notion that this mechanism is causal. We will also test whether the genetic signature that favours generation of new neurons in the hippocampus additionally predicts patient response to antidepressants. Such an association would provide pivotal evidence towards understanding antidepressant mode of action. The two main benefits from this research include: (i) improving our understanding of which mechanisms are truly causal to major depression, which would allow for more focused research in the future and the development of preventative strategies; (ii) improving our understanding of what factors moderate antidepressant response, which may allow for the stratification of patient treatment, and the development of "add on" drugs for those genetically predisposed to respond poorly to antidepressants. Improvements in each of these two areas could save the lives of depressed patients who are at risk of suicide by providing interventions or effective treatment faster, Moreover, it could save the UK millions of pounds wasted on ineffective treatments and loss of working hours.