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

Abstract

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.

The interaction of 5‐HTT variation, recent stress, and resilience on current anxiety levels in adolescents and young adults from the general population

“…This illustrates that the L A L A genotype might rather constitute a “plasticity” factor than a “risk” genotype. The present extended, three‐dimensional GxE approach incorporating the buffering effect of resilience‐increasing environmental factors (c.f., Schiele, Herzog, Kollert, Schartner et al, 2020) might thus aid in reconciliating incongruent or non‐replicable two‐dimensional 5‐HTT GxE studies (e.g., Border et al, 2019).…”

“…Recently, an extended approach to the GxE interaction model to include coping (C) characteristics in GxExC model (c.f., Schiele, Herzog, Kollert, Schartner et al, 2020) has highlighted the necessity of considering both advantageous and disadvantageous influences in shaping anxiety risk. High levels of general self‐efficacy were observed to buffer an otherwise increased vulnerability to anxiety as conferred by the interaction of childhood adversity and 5‐HTT LPR genotype (Schiele, Ziegler et al, 2016).…”

Oxytocin Receptor Gene DNA Methylation: A Biomarker of Treatment Response in Obsessive-Compulsive Disorder?

“…Healthy controls (n = 113; age: 33.63 ± 10.12 years; 57 females) of Caucasian background without a history of mental disorder matched for age and sex to the patient group were recruited at the Department of Psychiatry, University of Würzburg, Germany, within the Collaborative Research Center SFB-TRR58 between 2013 and 2016 [18,19].…”

Role of the Neuropeptide S System in Emotionality, Stress Responsiveness and Addiction-Like Behaviours in Rodents: Relevance to Stress-Related Disorders

“…A genotype-dependent association was found between the SNP rs324981, coping abilities and personality traits following adversity (see summary in Table 4 ). For example, women carrying the TT genotype and that experienced childhood maltreatment showed increased trait anxiety symptoms independently of general self-efficacy, which is a measure of coping abilities [ 102 ]. As for women carriers of the A allele that experienced childhood maltreatment, they showed increased anxiety symptoms only if they presented with low self-efficacy [ 102 ].…”