Mediating Effect of Genome-Wide Methylation in Conferring Risk for Suicide in Schizophrenia: A 1-year Follow-Up Study Monitoring Stress Exposure

Aim

The proposed project will investigate genome-wide methylation changes and stressful events as predictors of suicidal ideation (SI) in schizophrenia (SCZ).
Hypothesis
Suicidal behavior is a function of the interplay between stressful events and genes. It has been argued that adverse life events can alter gene expression resulting in improper functioning of neuronal circuitry and increased susceptibility to suicidal behavior. In this regard, epigenetic regulation has been considered the mechanistic interface between environmental stressful stimuli and altered functioning of underlying gene networks that may increase susceptibility to suicidal behavior.

Background

Approximately 5% of SCZ patients die by suicide. Genes play a rather important role in mediating the influence of stressful life experiences on suicidal behavior. Furthermore, there is also increasing evidence of epigenetic mechanisms influencing suicidal behavior. Among the epigenetic modifications, DNA methylation is the most studied and easily detectable when surveying the entire genome.

Methods

We aim to investigate DNA methylation changes that mediate the effect of stress exposure in triggering SI. Our specific objective is to investigate genome-wide methylation by analyzing longitudinal changes that confer risk for SI in SCZ. Genome-wide methylation patterns will be measured in 930 patients with SCZ assessed for SI. This study will identify the molecular mechanisms underlying SI by measuring methylomic changes and stress exposure at study entry, and 1-year follow-up. Longitudinal changes in DNA methylation will be measured in white blood cells as a potential peripheral marker of the biological effect of stress on SI. In the next two years, we will recruit 300 SCZ subjects from the Centre for Addiction and Mental Health (CAMH) and St. Michael's Hospital (SMH) in Toronto. We will analyze these newly recruited subjects together with a sample of 630 subjects that we have already recruited at CAMH. DNA samples will be collected for MethylationEPIC array profiling to determine genome-wide methylation. SI severity will be the primary outcome variable in a mediation model, with methylation changes and stressful events as predictors.

Significance

This study will be one of the first to investigate stress exposure as a causal factor of dynamic methylation changes across the genome, that in turn, trigger suicidal thoughts. Our results will suggest that there is variation in DNA methylation associated with exposure to stressful events. The main outcome of this grant would be to elucidate the molecular mechanisms that link stress to SI. Furthermore, a secondary outcome will be the identification of measurable epigenetic modifications as robust biomarkers associated with SI. Thus, the methylation sites that we aim to identify will serve as biomarkers with high translational value. Furthermore, potential proof of concept interventions in reducing SI could be validated by monitoring the methylation change in specific sites highlighted in this study. Finally, by identifying compelling candidate genes and biological pathways underlying SI in SCZ, our proposed study will highlight novel and potentially druggable molecular targets for the treatment of SI in SCZ.