Elsevier

Biological Psychiatry

Volume 86, Issue 6, 15 September 2019, Pages 433-442
Biological Psychiatry

Review
Genetics of Resilience: Gene-by-Environment Interaction Studies as a Tool to Dissect Mechanisms of Resilience

https://doi.org/10.1016/j.biopsych.2019.04.025Get rights and content

Abstract

The identification and understanding of resilience mechanisms holds potential for the development of mechanistically informed prevention and interventions in psychiatry. However, investigating resilience mechanisms is conceptually and methodologically challenging because resilience does not merely constitute the absence of disease-specific risk but rather reflects active processes that aid in the maintenance of physiological and psychological homeostasis across a broad range of environmental circumstances. In this conceptual review, we argue that the principle used in gene-by-environment interaction studies may help to unravel resilience mechanisms on different investigation levels. We present how this could be achieved by top-down designs that start with gene-by-environment interaction effects on disease phenotypes as well as by bottom-up approaches that start at the molecular level. We also discuss how recent technological advances may improve both top-down and bottom-up strategies.

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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