Extending the vulnerability-stress model of mental disorders: three-dimensional NPSR1 × environment × coping interaction study in anxiety

Br J Psychiatry. 2020 Nov;217(5):645-650. doi: 10.1192/bjp.2020.73.


Background: The general understanding of the 'vulnerability-stress model' of mental disorders neglects the modifying impact of resilience-increasing factors such as coping ability.

Aims: Probing a conceptual framework integrating both adverse events and coping factors in an extended 'vulnerability-stress-coping model' of mental disorders, the effects of functional neuropeptide S receptor gene (NPSR1) variation (G), early adversity (E) and coping factors (C) on anxiety were addressed in a three-dimensional G × E × C model.

Method: In two independent samples of healthy probands (discovery: n = 1403; replication: n = 630), the interaction of NPSR1 rs324981, childhood trauma (Childhood Trauma Questionnaire, CTQ) and general self-efficacy as a measure of coping ability (General Self-Efficacy Scale, GSE) on trait anxiety (State-Trait Anxiety Inventory) was investigated via hierarchical multiple regression analyses.

Results: In both samples, trait anxiety differed as a function of NPSR1 genotype, CTQ and GSE score (discovery: β = 0.129, P = 3.938 × 10-8; replication: β = 0.102, P = 0.020). In A allele carriers, the relationship between childhood trauma and anxiety was moderated by general self-efficacy: higher self-efficacy and childhood trauma resulted in low anxiety scores, and lower self-efficacy and childhood trauma in higher anxiety levels. In turn, TT homozygotes displayed increased anxiety as a function of childhood adversity unaffected by general self-efficacy.

Conclusions: Functional NPSR1 variation and childhood trauma are suggested as prime moderators in the vulnerability-stress model of anxiety, further modified by the protective effect of self-efficacy. This G × E × C approach - introducing coping as an additional dimension further shaping a G × E risk constellation, thus suggesting a three-dimensional 'vulnerability-stress-coping model' of mental disorders - might inform targeted preventive or therapeutic interventions strengthening coping ability to promote resilient functioning.

Keywords: Resilience; anxiety disorder; differential susceptibility; general self-efficacy; neuropeptide S receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Psychological*
  • Adult
  • Anxiety / genetics*
  • Anxiety / psychology*
  • Anxiety Disorders / genetics*
  • Anxiety Disorders / psychology*
  • Female
  • Gene-Environment Interaction*
  • Genotype
  • Humans
  • Male
  • Receptors, G-Protein-Coupled / genetics*
  • Self Efficacy


  • NPSR1 protein, human
  • Receptors, G-Protein-Coupled