The implications of gene–environment interactions in depression: will cause inform cure?

Abstract

In a number of human diseases, including depression, interactions between genetic and environmental factors have been identified in the absence of direct genotype-disorder associations. The lack of genes with major direct pathogenic effect suggests that genotype-specific vulnerabilities are balanced by adaptive advantages and implies aetiological heterogeneity. A model of depression is proposed that incorporates the interacting genetic and environmental factors over the life course and provides an explanatory framework for the heterogeneous aetiology of depression. Early environmental influences act on the genome to shape the adaptability to environmental changes in later life. The possibility is explored that genotype-and epigenotype-related traits can be harnessed to develop personalized therapeutic interventions. As diagnosis of depression alone is a weak predictor of response to specific treatments, aetiological subtypes can be used to inform the choice between treatments. As a specific application of this notion, a hypothesis is proposed regarding relative responsiveness of aetiological subtypes of depression to psychological treatment and antidepressant medication. Other testable predictions are likely to emerge from the general framework of interacting genetic, epigenetic and environmental mechanisms in depression.

Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project

“…It has been suggested that such a subgroup would respond better to psychotherapy than antidepressants. 35 Our results are consistent with this suggestion; specifically, the 'reactive' subgroup showed a markedly poorer response to escitalopram than their 'endogenous' counterparts. These effects were not seen in the nortriptyline-treated patients.…”

The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update

“…The relationship between the method of adversity assessment and results held almost perfectly: all studies using objective indicators or structured interviews to assess stress replicated the gene-environment interaction fully or partially, whereas all non-replications relied on brief self-report measures of adversity (Table 1). This relationship between the method used to assess environmental adversity and results was statistically significant (w 2 (1) test for trend = 8.51, P = 0.004). This result held across a range of sensitivity analyses probing the influence of review methodology: inclusion of studies with small sample size and with neurological illness or reclassification of studies with interviewer-aided administration of a questionnaire as interviews strengthened this result.…”

“…This result held across a range of sensitivity analyses probing the influence of review methodology: inclusion of studies with small sample size and with neurological illness or reclassification of studies with interviewer-aided administration of a questionnaire as interviews strengthened this result. The preponderance of non-replications and partial replications in adolescent samples also held for the updated list of 34 studies (w 2 (1) test for trend = 5.30, P = 0.02; Table 1). Most part-replications in adolescent samples found the gene-environment interaction in female but not male adolescents.…”

“…1 The fact that these gene-environment interactions are often not accompanied by direct gene-illness associations suggests a reason why genome-wide association studies may not detect genes involved in the causation of mental disorders. 2 As researchers are contemplating the need for and feasibility of including environmental factors in genome-wide searches for causative mechanisms, the replicability of gene-environment interactions has become topical. A primary focus has been on the interaction of a length polymorphism in the serotonin transporter gene (5-HTTLPR) and environmental adversity in the causation of depression.…”

Learning not to Fear: Neural Correlates of Learned Safety

“…Such studies have shown that genetic risk factors increased the probability for major depression and had a higher impact on females than males (Kendler, 2001). Furthermore, specific gene variants (eg serotonin transporter, pituitary adenylate cyclaseactivating polypeptide (PACAP), and PAC1 receptor) have also found to influence the susceptibility as well as resilience to develop mood disorders (Mahan and Ressler, 2012;Uher, 2008). However, whether and how these and other genetic risk factors together with other factors, such as age, sex, and environmental conditions, may also have a role in regulating learned safety remain to be elucidated in future studies.…”