Abstract
 

Genomic and exposomic drivers of mental health trajectories and resilience

There is active interest in understanding the relationship between neuropsychiatric disorders and modifiable and potentially preventable environmental exposures. However,
mental disorders have complex pathoetiology involving genetic and environmental risk factors, as well as their interactions. For instance, our recent series of work using polygenic risk score for schizophrenia has provided molecular evidence for gene-environment interaction in psychosis. We showed that genetic liability to psychosis moderated the influence of several environmental factors, such as cannabis use and childhood adversities, to increase psychosis risk.  Moving from candidate genes to genome-wide approaches has increased the replicability of genetics research. However, the complexity of the environment, involving many causal and noncausal pathways, continues to make research challenging.   

To tackle these challenges, we have recently proposed the use of the exposome paradigm. The exposome represents the totality of exposures in a lifetime from conception onward. The framework offers a solution to handle the complexity of all “non-genetic” factors. We recently adopted the exposome approach to construct an exposome score for schizophrenia (ES-SCZ). Our findings demonstrate that ES-SCZ can be used for risk stratification, adjusting for cumulative environmental load in statistical testing, and collecting risk enriched cohorts. Increasing data availability will help improve ES-SCZ that can be used in staging models to enhance clinical characterization and outcome forecasting.

Although ES-SCZ already provides several practical benefits for research practice, the exposome paradigm offers much more. Agnostic exposome-wide analyses might be the first step to mapping the exposome of mental health phenotypes. In the UK Biobank, we showed that an exposome-wide study followed by Mendelian Randomization analyses might help distinguish genuine signals from selective reporting and uncover novel risk and resilience factors.  The exposome approach will also increase our understanding of the differential impact of the environment on mental health across geographical settings and ethnic communities. We are in the early phases of exposome research in psychiatry; however, if successfully applied, the exposome framework is poised to embrace complexity and enable advanced analytical solutions to harness ever-growing data to gain insight into the complex dynamic network of exposures.

As the logical continuation of our research line, our research team aims to integrate exposomic, genomic, and epigenomic data to execute the next phase of gene-environment research to provide clues for potentially modifiable factors, increase mechanistic understanding of trans-syndromal risk and resilience trajectories over the lifetime, and translate these findings into clinical practice to transform the prevention and treatment of mental disorders.