Common genetic variation impacts stress response in the brain

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Individual responses to identical stressors vary, suggesting a role for molecular mechanisms in mediating clinical outcomes.
• Genetic predisposition interacts with environmental factors like stress to influence brain disorder development.

Approach:

• Analyzed post-mortem brain tissue (n=304) to identify stress-interactive expression quantitative trait loci (eQTLs).
• Validated findings in human induced pluripotent stem cell (hiPSC)-derived neurons treated with glucocorticoids.
• Investigated brain region- and cell type-specific stress responses, implicating glial and endothelial cells.

Key Points:

• Identified 8557 stress-interactive eQTLs affecting 915 genes (eGenes) in response to stress.
• Up to 50% of stress-interactive eGenes were validated in hiPSC-derived neurons.
• Discovered 139 novel brain disorder risk genes by imputing stress-interactive transcriptomic data.

Conclusions:

• Molecular encoding of stress explains individualized responses to traumatic stress.
• Integrating trauma into genomic studies can enhance diagnosis, prognosis, and drug discovery for brain disorders.