Depression, Inflammation, and Atopy: Examining a Complex Relationships Using Genetic Epidemiology

Abstract

Depression is a common psychiatric disorder characterized by low mood, fatigue, concentration problems, and feelings of worthlessness. According to the World Health Organization, depression is the leading cause of disability worldwide. Depression is also associated with increased risk for a variety of medical conditions over the life course. While the exact etiologic mechanisms are unknown, depression is thought to involve interactions between a complex set of social, environmental, biological, and genetic risk factors.

The overarching theme of this dissertation is to use genetic methods to explore etiologic hypotheses about depression and its comorbidities. Genetic factors can influence depression risk, both directly and indirectly at multiple levels, including biological, behavioral, and the broader social and physical environment. The involvement of genetic influences in almost every layer of disease development makes genetic epidemiology a powerful tool for studying conditions such as depression that have complicated networks of contributing factors.

The first empirical chapter in the dissertation examines the relationship between atopic disorders (disorders involving inappropriate immune reactivity to benign stimuli, such as allergies and asthma) and psychiatric disorders, including depression. Although there is a known association between atopic disorders and depression, the relationship between atopic disorders and other psychiatric disorders is not as clearly established. Assessing this relationship is further complicated by the high levels of comorbidity between psychiatric disorders. Using data from a large, US-based sample, this chapter confirms the relationships between atopic disorders and a range of psychiatric disorders and determines that the relationships persist after adjustment for comorbid psychiatric disorders.

The second empirical chapter tests the hypothesis that there is a causal effect of interleukin-6 (IL-6) signaling on depression. IL-6 is a cytokine that plays numerous roles throughout the body, including pro-inflammatory signaling. Existing cross-sectional and longitudinal studies have report associations between elevated IL-6 and depression, and there are plausible biological mechanisms for how this cytokine may contribute to depression. Using data from the United Kingdom (UK) Biobank, a large genotyped sample of UK adults, this chapter applies a Mendelian Randomization design to assess whether IL-6 signaling has a causal effect on depression. It finds evidence consistent with a causal effect of IL-6 signaling on depression, and that this relationship is likely to due to signaling via the soluble form of the IL-6 receptor.

The final empirical chapter applies multiple genetic analyses to explore competing explanatory models for the comorbidity between depression and atopic disorders, again within the UK Biobank sample. This chapter examines several potential explanations, including shared genetic liability, causal effects of atopic disorders on depression, differential self-reporting of atopy by individuals with depression, and lowering of the threshold for atopic responses among individuals with depression. From these analyses, this chapter shows that shared genetic influences on atopy and depression are likely, and that multiple explanations may contribute to the relationship simultaneously.

In sum, this dissertation illustrates that by using a variety of study designs from both traditional observational and genetic epidemiology, etiologic questions can be examined from multiple angles to produce a more robust understanding of complex relationships, such as the relationships between depression, inflammation, and atopy. This has resulted in several interesting findings, including that the relationship between atopic disorders and depression is at least partially explained by shared genetic liability, and that interleukin-6 inflammatory signaling is likely to have a causal effect on depression.