Elsevier

Psychiatry Research

Volume 304, October 2021, 114139
Psychiatry Research

Review article
Genetic markers of the stress generation model: A systematic review

https://doi.org/10.1016/j.psychres.2021.114139Get rights and content

Highlights

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    Robust evidence suggests that depression, and risk for depression, are associated with the generation of stressful life events.

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    This systematic review aimed to identify specific molecular genetic markers associated with the generation of stressful life events.

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    There is evidence that genetic variation in the serotonin, HPA axis, and oxytocin systems moderates the effects of psychosocial vulnerability markers on the generation of proximal, dependent life events.

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    Future research should examine additional genetic markers in systems known to confer risk for stress generation.

Abstract

Aim

Robust evidence suggests that depression, and risk for depression, are associated with the generation of stressful life events. This tendency to generate stress may be genetically determined. This systematic review aimed to identify specific molecular genetic markers associated with the generation of interpersonal stressful life events, at least in part dependent on individuals’ behavior.

Method

We followed the PRISMA guidelines in searching six electronic databases (PubMed, MEDLINE, PsycINFO, CINAHL, Cochrane, and EMBASE) from inception to January 2021, and we reviewed the reference lists of eligible articles for additional records. We restricted eligibility to empirical studies involving at least one genetic marker and including proximal life events. We evaluated the risk of bias using the Newcastle Ottawa Scale for observational studies. The outcome permitted a distinction between life events dependent on the individual's agency versus independent events.

Results

Seven studies, including 3585 participants, met eligibility criteria. Three were longitudinal, and four were cross-sectional; six included adolescents and young adults, and one focused on middle adulthood. Four examined the serotonin-transporter-linked promoter region (5-HTTLPR), two examined the rs53576 single nucleotide polymorphism of the oxytocin receptor gene (OXTR), and one examined a multilocus genetic profile score including four hypothalamic-pituitary-adrenal (HPA) axis genes. There were no significant direct correlations between genotype and life events in any study. Instead, their relation was significantly moderated by symptoms, exposure to early adversity, or attachment. Consistent with the stress generation hypothesis, this moderation relation was significant in predicting exposure to dependent life events but was not significant in predicting independent life event exposure.

Conclusions

There is evidence that genetic variation in the serotonin, HPA axis, and oxytocin systems moderates the effects of psychosocial vulnerability markers on the generation of proximal, dependent life events. Future research should examine additional genetic markers in systems known to confer risk for stress generation.

PROSPERO

CRD42019136886.

Section snippets

Background

Globally, depression affects nearly 300 million people and is the worldwide leading cause of morbidity (Herrman et al., 2019). Exposure to stressful life events (SLEs) is the strongest proximal trigger of depression onset. Careful prospective behavioral genetic research shows that the association between SLEs and depression is causal (Kendler et al., 1999). Exposure to life events is not random, however. A key driver of this vulnerability is the tendency of depression-vulnerable individuals to

Protocol and registration

We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Liberati et al., 2009). In addition, we registered this review using PROSPERO (CRD42019136886).

Eligibility criteria

Eligible studies examined the relation of one or more genetic markers to the generation of proximal SLEs. We defined a genetic marker as any DNA sequence that causes disease or is associated with an illness (Wikipedia, 2021). We defined proximal SLEs as stressful life events occurring within 12

Study selection

Seven studies (Starr et al., 2012, 2013; Thompson et al., 2014; Harkness et al., 2015; Brinksma et al., 2018; Ebbert et al., 2019; Huang and Starr, 2020) met the eligibility criteria for the systematic review (Fig. 1).

Characteristics of studies

We provide the characteristics of all studies in Table 1. Three studies included longitudinal designs (Brinksma et al., 2018; Starr et al., 2013, 2012) while the remaining four were cross-sectional (Thompson et al., 2014; Harkness et al., 2015; Ebbert et al., 2019; Huang and

Discussion

The purpose of the current systematic review was to critically review studies examining the molecular genetic markers associated with exposure to specific environments that are at least in part dependent upon or generated by the individual. Consistent with the stress generation hypothesis, all seven studies in the current review found evidence for a significant relation of genetic risk to exposure to dependent stressors, particularly in the interpersonal domain. In contrast, none of the five

Conclusions

The current systematic review is the first to integrate and critically evaluate the literature on the relation of molecular genetic markers to the generation of SLEs. Compared with the body of literature examining gene-by-environment interaction in predicting psychopathology, the gene-stress generation literature is in its infancy. Only seven studies were identified that examined the relation of genetic markers to SLEs relevant to stress generation (i.e., SLEs at least in part dependent on the

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    • Cited by (0)

    Acknowledgments: We would like to acknowledge the University of Calgary Health Sciences Librarians for their support in developing our search strategy.

    Disclosure: Dr. Bahji is a recipient of the 2020 Friends of Matt Newell Endowment in Substance Abuse through the University of Calgary's Cumming School of Medicine.

    Funding Sources: none.

    Role of Authors: All the authors contributed to this study's design, interpreting the data, subsequent manuscript drafts (and revisions), and final approval for submission. Two co-authors conducted the initial systematic review (EB and AB). One author (AB) wrote the initial draft of the work and managed revision feedback from the other authors. Finally, one co-author supervised and provided contextualized input throughout all stages of the manuscript's generation (KH).

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