A Life-course Analysis of Gene-Environment Interplay in Schizophrenia and Major Depression

Background: Although genetic and environmental risk factors for schizophrenia (SCZ) and major depressive disorder (MDD) are well established, it is not clear whether the exposure to these environmental risks is genetically confounded through a mechanism known as gene- environment correlation (rGE). Identifying whether rGE is implicated in the aetiology of these two psychiatric disorders may help our understanding of how to treat or prevent psychopathologies. Objective: This thesis aimed to investigate whether known environmental risk factors are correlated with the genetic susceptibilities to SCZ/MDD across three British community cohorts in childhood, adulthood and across the different developmental periods over time. We also wished to compare findings from a systematic literature review of empirical rGE studies for SCZ and depression to our own results. Methods: Polygenic risk scores (PRS), which were derived from existing genome-wide associations studies (GWAS), were utilised to investigate the correlation between known environmental risk factors and the genetic liability to SCZ/MDD. For the systematic literature review we searched seven databases for publications reporting rGE for either psychopathology in participants of any age. Results: We found associations between the genetic risk for SCZ and several psychosocial risk factors, such as marital status, whilst the genetic susceptibility to MDD was more strongly correlated with indicators of adverse socio-economic status across childhood and adulthood. Overall, the majority of rGE correlations remained stable across the investigated developmental periods. In contrast to our own results, rGE associations for SCZ and depression which were identified in the systematic literature review were largely the same across the included articles. Conclusion: In summary, our findings propose that several known psychosocial and environmental risk factors for either SCZ or MDD are at least partially correlated with the genetic liability for these psychopathologies in childhood as well as adulthood

Polygenic risk scores for schizophrenia and major depression are associated with socio-economic indicators of adversity in two British community samples

Schizophrenia (SCZ) and major depressive disorder (MDD) are complex psychiatric disorders which contribute substantially to the global burden of disease. Both psychopathologies are heritable with some genetic overlap between them. Importantly, SCZ and MDD have also been found to be associated with environmental risk factors. However, rather than being independent of genetic influences, exposure to environmental risk factors may be under genetic control, known as gene-environment correlation (rGE). In this study we investigated rGE in relation to polygenic risk scores for SCZ and MDD in adults, derived from large genome-wide association studies, across two different British community samples: Understanding Society (USoc) and the National Child Development Study (NCDS). We tested whether established environmental risk factors for SCZ and/or MDD are correlated with polygenic scores in adults and whether these associations differ between the two disorders and cohorts. Findings partially overlapped between disorders and cohorts. In NCDS, we identified a significant correlation between the genetic risk for MDD and an indicator of low socio-economic status, but no significant findings emerged for SCZ. In USoc, we replicated associations between indicators of low socio-economic status and the genetic propensity for MDD. In addition, we identified associations between the genetic susceptibility for SCZ and being single or divorced. Results across both studies provide further evidence that the genetic risk for SCZ and MDD were associated with common environmental risk factors, specifically MDD’s association with lower socio-economic status

Gene-Environment Correlation over Time: A Longitudinal Analysis of Polygenic Risk Scores for Schizophrenia and Major Depression in Three British Cohorts Studies

Research suggests that both genetic and environmental risk factors are involved in the aetiology of schizophrenia (SCZ) and major depressive disorder (MDD). Importantly, environmental and genetic risk factors are often related as evidenced in gene–environment correlation (rGE), which describes the observation that genetic and environmental factors are associated with each other. It is understood that rGE gets stronger over time as individuals select their environments more actively based on their genetic propensities. However, little is known whether rGEs remain stable over time or change across different development periods. Using data from three British longitudinal cohorts, we investigated whether rGE patterns of polygenic risk scores (PRS) for SCZ and MDD changed over time across childhood and adulthood, as well as across both from birth to age 55 and whether results differed between SCZ and MDD. Overall, the majority of rGEs remained stable across the investigated development periods. Furthermore, the few detected rGE changes which did differ between SCZ and MDD, could not be explained by the confounding of clinical cases and are therefore likely the result of actual changes in environmental and cultural risk factors with genetic susceptibility to SCZ and MDD likely playing a less significant role