Plenary talk by Michael Meaney from McGill University during the 74th SOBP Annual Meeting in Chicago, Illinois from May 15 - 18, 2019. The Genomic Architecture of Individual Differences in Stress Susceptibility Stress is a well-established ‘trigger’ for multiple forms of chronic illness including mental disorders. Despite the compelling epidemiological evidence, most individuals exposed to chronic, severe stress during development or adulthood are largely unaffected with respect to serious health outcomes. These findings reflect the remarkable individual variation in susceptibility to stress. In the studies reported here we attempted to integrate this knowledge into an analysis of the genetic architecture of stress susceptibility in humans. We used a publicly-available, genome-wide association study of addictions that included measures of environmental adversities known to increase the risk for psychopathology. We identified individual single-nucleotide polymorphisms (SNPs) that distinguished adversity-exposed individuals with (susceptible) or without (resilient) substance abuse in a training data set. The resulting SNPs were to develop a genomic profile score for stress susceptibility (GPSsus) that was subsequently validated in a test dataset. The resulting GPSsus also predicted adversity-related mental disorders in multiple independent samples of individuals exposed to early life adversity. The GPSsus genes are highly enriched for SNP’s associated with levels of DNA methylation, suggesting epigenetic mediation. Animal models identify transcriptional pathways and neural circuits associated with individual differences in susceptibility to adversity. We used one such model, chronic social defeat, and found a highly significant overlap between the genes that comprised our GPSsus and differentially expressed genes using RNAseq from the ventral hippocampus in resilient vs susceptible mice. Informatic analyses of both human and rodent data sets implicate both estrogen- and glucocorticoid-signalling pathways. Direct manipulation of ESR1 expression resulted in significant alterations in stress susceptibility in the murine chronic social defeat model. In sum, our findings reveal a distinct genetic architecture that underlies individual differences in susceptibility to adversity in humans. Functional genomic analysis implies a role for brain region-specific, steroid-sensitive transcriptional signalling in defining individual differences in susceptibility to stress.
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