Genetic responses to environmental stress underlying major depressive disorder
Arnau Soler, Aleix
Major depressive disorder (MDD) is a common psychiatric disorder and a leading cause of disability worldwide. Such illness is the result of a complex interplay between genetic susceptibility and environmental risk factors. Adverse life events are experienced before the onset of depressive episodes in most patients, with robust evidence for the role of stressful life events (SLE) as a main trigger of depressive symptoms. However, not all individuals develop depression after episodes of stress. Thus, an individual’s sensitivity to stress is an important predictor of stress response that may mediate the association between stress and depression. A deeper understanding of the genetic mechanisms underlying stress-sensitivity and stress response is, therefore, crucial to a better understanding of MDD and thus to improve treatments for both depressive symptoms and other stress-related conditions. This PhD thesis uses empirical data from white Caucasian population-based samples. By incorporating in new hypothesis-free genome-wide association studies and polygenic approaches quantitative measures of recent SLE and neuroticism---a personality trait though to mediate or moderate the effects of adversity on depression risk---, this PhD thesis identifies the genetic influences to a proxy for sensitivity to environmental stress and genotype-byenvironment interaction (GxE) effects underlying depressive symptoms. Following an introductory chapter, chapter 2 conceptualizes a proxy for our sensitivity to negative outcomes by modelling the interaction between genetic variants and MDD status on neuroticism score through a genome-wide interaction study. This chapter seeks to identify genetic variants contributing to a potential endophenotype mediating the associations between stress and depression, and examines whether genetic effects on such proxy for stress sensitivity partially explains the genetic contributions to liability not attributable to additive main effects. The strongest signals came from genetic variants associated with the glucocorticoid receptor function. Therefore, Chapter 3 assesses the enrichment of the genetic contributions to liability of MDD within three glucocorticoid-related gene sets: one gene set reflecting “up-stream” cortisol signalling genes and two gene sets reflecting “downstream” cortisol response genes. Chapter 4 empirically tests and assesses the diathesis-stress theory for depression; using polygenic risk scores weighted by the additive effects of MDD derived from the Psychiatric Genetic Consortium MDD genome-wide association study and self-reported measures on recent SLE. This chapter provides evidence for the presence of GxE effects between stress and common genetic variants on risk of depressive symptoms. The empirical support for this theory validates other GxE approaches applying a genome-wide approach to investigate the causative effect of stress in the development of depressive symptoms. Thus, chapter 5 presents findings from genome-wide by environment interaction studies in two cohorts that seek to identify common variants displaying an increased risk of liability to depressive symptoms in response to SLE. Whether inclusion of GxE effects improves the prediction of liability to MDD over that explained by genetic additive main effects alone is also tested. Furthermore, two potential forms of gene-environment interplay (i.e. GxE and gene-environment correlation) and their biological interpretation are extensively discussed. Stress contributes to many human conditions. Therefore, the GxE effects are also used to predict other stress-related physical and mental conditions. This chapter reports evidence of a potential shared aetiology between depression and other traits, such as schizotypal personality or heart disease, due to genetic mechanism underlying the effects of SLE. Finally, chapter 6 brings back the diathesis-stress model investigated in chapter 4. This chapter incorporates into the diathesis framework the genetics effects for stress sensitivity and stress response estimated in chapters 2 and chapter 5, respectively, and assess their relevance to the diathesis-stress theory. Genetic differences between women and men in stress response underlying the aetiology of depression are also discussed. Genetics plays a significant role in the effects of stress. The findings presented in this thesis emphasize the relevance of genetic effects for stress sensitivity and stress response in depression and health in general. Overall, this thesis presents a range of original studies in order to advance our understanding of the genetic response to stress, comprehensively discussing the limitations and pitfalls of this research area, and provides a basis for future lines of research on gene-environment interplay in psychiatry.