Using genetics to understand the complex relationships between metabolic and mental health in diverse global settings

Abstract

Obesity and psychiatric diseases are global health challenges and leading causes of disease burden and disability worldwide. There is extensive evidence linking higher body mass index (BMI) to higher odds of depression, anxiety, and lower well-being in adults of European (EUR) ancestry. Whilst several studies have attempted to test the directionality of associations between adiposity and mental health phenotypes, determining causality in many studies is not trivial due to confounding or biases. An alternative method to identify exposures that causally affect mental health and well-being is Mendelian Randomisation (MR), where genetic variants shown to be associated with an exposure are used as instruments to measure the effect on the outcome. Understanding the complex relationships between adiposity and mental health outcomes is crucial to facilitate public health and medical intervention planning. MR can also provide important information about whether and how the relationship differs across cultural settings (‘setting-specific causality’), and therefore whether the appropriate public health response should also differ. The primary aim of this thesis is to further explore the relationship between adiposity and mental health and well-being in diverse ancestry populations.

This work has provided genetic evidence to support the idea that the sociocultural consequences of obesity are relevant to the relationship between BMI and mental health and well-being. This thesis has demonstrated the importance of extending genetic causal inference analyses to diverse ancestries, as relationships may vary across different cultural contexts. This PhD project shows that it is essential to increase the ancestral and geographic diversity of samples in genetic studies, as well as consider non-linear models in MR analyses, in order to gain a fuller understanding of the relationship between obesity and mental health or well-being. Finally, this thesis has demonstrated the complexity of the relationship between obesity and mental health or well-being, and the potential role of other factors, e.g., chronotype, in this relationship.