Abstract
To understand the role of environment in the pathoetiology of psychosis spectrum disorders, research has thus far mainly investigated the effects of single exposures in isolation, such as the association between cannabis use and schizophrenia. However, this approach fails to acknowledge the complexity of the exposome, which represents the totality of the environment involving many exposures over an individual's lifetime. Therefore, contemporary research adopting the exposome paradigm has aimed at capturing the combined effect of different environmental exposures by utilizing an aggregate environmental vulnerability score for schizophrenia: the exposome score for schizophrenia. Here, we attempt to provide a comprehensive overview of studies applying the exposome score for schizophrenia. First, we describe several approaches estimating exposomic vulnerability for schizophrenia, which falls into three categories: simple environmental sum scores (sum of dichotomized exposures), meta-analysis-based environmental risk score (sum scores weighted by estimates from meta-analyses), and the exposome score (sum score weighted by estimates from an analysis in an independent training dataset). Studies show that the exposome score for schizophrenia that assumes interdependency of exposures performs better than scores that assume independence of exposures, such as the environmental sum score and the meta-analysis-based environmental risk score. Second, we discuss findings on the pluripotency of the exposome score for schizophrenia and summarize findings from gene-environment studies using the exposome score for schizophrenia. Finally, we discuss possible scientific, clinical, and population-based applications of exposome score for schizophrenia, as well as limitations and future directions for exposome research to understand the etiology of psychosis spectrum disorders.
Highlights
Psychosis spectrum disorders (PSD) have a complex pathoetiology involving genetic and environmental factors
A study investigating the “vibration of effects” showed that results in analytical models of exposures were dependent on the model specifications, such as the inclusion of different sets of variables [8]. These findings show that environmental vulnerability for PSD cannot be understood in isolation
Results are from Pries et al [22] analyses associating a simple sum score, a score based on meta-analyses, and ES-SCZ including the same environmental exposures withcase-control status; ES-SCZ, exposome score for schizophrenia; ROC, area under the receiver operating characteristic curve, Explained variance: Nagelkerke’s pseudo R2
Summary
Psychosis spectrum disorders (PSD) have a complex pathoetiology involving genetic and environmental factors. Studies indicate that the molecular genetic vulnerability for schizophrenia captured by PRS-SCZ only explains 7.7% of the variance in liability attributable to schizophrenia, with the SNP-based heritability being around 24% [2] These are considerably below the 60–80% heritability estimates previously demonstrated in family and twin studies [3,4,5,6]. This “heritability gap” is a strong indicator that at least part of the pathoetiology for schizophrenia may be explained by environmental factors [7], besides other explanation such as gene-gene interactions
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