ReviewGenetics of Resilience: Gene-by-Environment Interaction Studies as a Tool to Dissect Mechanisms of Resilience
Section snippets
G×E Mapping to Identify Common Mechanisms: Diagnoses to Intermediate Phenotypes
Different conceptional frameworks of how genomic determinants moderate environmental risk have evolved over time. Initially, G×E studies were framed within the diathesis–stress model, which posits that cumulative environmental adversity eventually will lead to dysfunction and that genetic (and other biological) variables determine the individual threshold of adversity necessary for dysfunction to occur. Resilience genotypes within this conceptualization heighten this threshold by affecting
Bottom-up Mapping of G×E: From Molecules to Intermediate Phenotypes to Diagnoses
Another avenue toward the identification of resilience mechanisms and intermediate phenotypes could follow a bottom-up approach that starts with mapping regulatory gene variants associated with heightened sensitivity to environmental stimuli on a molecular level.
Exposure to environmental stimuli leads to a cascade of effects that, in the case of adversity, culminates in the activation of stress response systems such as the catecholaminergic system and the stress hormone system. This leads not
Future Directions
Studying G×Es may provide a tool to dissect mechanisms of resilience. Studies exploring G×E on diagnostic outcomes have had a major conceptual impact on the field 13, 81 but are fraught with issues of lack of replication. This relates to power issues, with initial discoveries in small samples, but also inherent problems of our field, with symptom-based and not mechanism-based diagnoses, increasing the heterogeneity within current diagnostic groups. In addition, current studies rarely rely on
Acknowledgments and Disclosures
This work was supported by an Alexander von Humboldt Fellowship and a Banting Postdoctoral Fellowship to CC.
EBB is coinventor of the patent application “FKBP5: A novel target for antidepressant therapy” (European Patent No. EP 1687443 B1). The other authors report no biomedical financial interests or potential conflicts of interest.
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