Suicide-associated Loci Regulating Molecular Traits and Their Interaction With Environmental Factors

As a major public health problem, suicidality is one of the leading causes of death and disability worldwide. Suicidality is a result of the interaction of several contributors, including genetic and environmental factors. The role of genetic factors in suicide is partially mediated by the effects of gene variants on gene expression and DNA methylation. The functional characterization of the suicidality-associated genetic variants and their associated molecular phenotypes will be helpful in the elucidation of the underlying pathophysiology of suicidality. Furthermore, the effect of genetic variants could be modulated by environmental factors. Even though several gene-environment interactions have been identified in suicidality, our knowledge of the molecular mechanisms mediating such interactions is limited. We hypothesize that gene-environment interactions in suicidality are, at least partially, mediated by genetically regulated gene expression and methylation. Here, we propose an integrative analysis of the interaction among genetic variants and their associated molecular phenotypes with environmental variables in suicidality. We will estimate the genetically regulated gene expression and DNA methylation in multiple brain regions, peripheral blood, and adrenal gland from the genotype of the UK Biobank (UKB) and the National Health and Resilience in Veterans Study (NHRVS) participants of diverse ancestral backgrounds (n=144,519). Then, we will test the associations using a logistic regression model between the genetically imputed gene expression/methylation levels and suicidality categories i.e., passive suicidal ideation, active suicidal ideation, non-suicidal self-injury, and suicide attempt. To identify relevant genes for each suicidality category, we will perform a co-expression/co-methylation network analysis using the genes whose gene expression/DNA methylation levels were found to be associated with suicidality categories. Then, we will identify relevant hub genes, which are those with a high degree of connectivity between them and are likely to play a key role in the association between genotype-suicidal traits. To identify genes with genetic variants influencing gene expression and/or DNA methylation that interact with suicidal behavior risk factors and infer a causal relationship between them, we will perform a gene-environment interaction analysis between the genetic variants influencing gene expression and/or DNA methylation in brain, blood, and adrenal gland, and suicide risk factors including traumatic experiences and psychiatric disorders. Then, we will perform a Mendelian randomization analysis to investigate whether changes in genetically regulated gene expression and DNA methylation may influence variations on suicidal behavior risk factors. The overall goal of our proposal is to characterize the downstream molecular consequences of suicidality-associated genetic variants influencing gene expression and DNA methylation, as well as to evaluate their interaction with environmental risk factors. Our results will improve our understanding of the mechanisms underlying genetic predisposition to suicidality. This study will permit us to identify genetic variants, whose effects are dependent on the level of exposure to a specific environment. This will ultimately lead to the identification of patients at high suicidal risk and the subsequent development of personalized preventive and therapeutic interventions.