Interactions between individual differences in gene expression and adverse experiences underlying susceptibility and resilience to depression - Rates of depression in adolescents are high (~24%). Early adversity exposure can affect brain development and function and lead to depression. However, only some youth, who may be less genetically resilient, develop psychopathology after adversity, suggesting neurobiological and genetic differences. Previous studies from our research team found in both mice and humans that depressive-like behaviors only developed after adversity, when the hippocampus was compromised. Moreover, using postmortem brains, the team found hippocampal genetic pathways associated with adversity exposure or resilience in mice and with depression in humans. This proposal will determine whether individual differences in expression of these genetic pathways in humans increases susceptibility, or conversely resilience, to adversity and thereby the likelihood that individuals will develop depression. The research team with expertise across basic neuroscience (rodents and humans), clinical and developmental psychology, translational epidemiology, statistical genomics and biostatistics is uniquely suited for this proposal, which sits at the intersection of neuroscience, genomics and epidemiology. Aim 1 will determine if innate differences in hippocampal adversity-, resilience- and depression-related gene expression pathways modify risk for depression after early adversity. However, levels of hippocampal gene expression cannot be directly measured in living humans. Therefore, first relevant hippocampal gene networks from causal mouse models and postmortem human brains will be defined. Then, we will use data from the Adolescent Brain Cognitive Development Study (the largest US longitudinal study of adolescent neurobiological development; n=11,700) and leverage innovative, data-driven “expression-based polygenic scores (ePGSs)”, which reflect individual variation in predicted hippocampal expression of the gene networks of interest. Using these techniques, we will determine if differences in expression of these gene networks (ePGSs) predict depression development after adversity exposure. In Aim 2, we will test how these genetic scores moderate possible mediation pathways between early adversity and depression through altered hippocampal and brain- wide task-based and resting-state connectivity. In Aim 3, we will test replication and extension of the findings to lifetime depression in a cohort of middle-aged adults (UK Biobank; n=500,000). Then, in both cohorts, lifestyle factors known to promote hippocampal function will be examined as modifiable mitigating factors for those with high depression risk. We hypothesize that individuals with highest genetic risk measured by ePGSs who have had substantial early adversity exposure, have altered hippocampal activity and increased risk for depression. By elucidating the interactions between genetic risks and environmental stressors, and how they affect brain function, we aim to identify the individuals most vulnerable to depression development after adversity to ultimately steer prevention efforts towards those who need it most, in line with the NIMH’s goals to better understand brain and genomic mechanisms underlying psychopathology and to prevent mental illness.
