Gene-environment interactions between HPA-axis genes and stressful life events in depression: a systematic review

Objective: Depression is a disorder caused by genetics and environmental factors. The aim of this study was to perform a review investigating the interaction between genetic variations located in genes involved in hypothalamus-pituitary-adrenal axis (HPA-axis) and stressful life events (SLEs) in depression. Methods: In this systematic review, we selected articles investigating the interaction between genes involved in the HPA-axis, such as Arginine Vasopressin (AVP), Angiotensin Converting Enzyme (ACE), Corticotrophin Releasing Hormone (CRH), Corticotrophin Releasing Hormone Receptor 1 (CRHR1), Corticotrophin Releasing Hormone Receptor 2 (CRHR2), FK506 binding protein (FKBP5), Nuclear Receptor subfamily 3 group C member 1 (NR3C1), Nuclear Receptor subfamily 3 group C member 2 (NR3C2), and SLE. The literature search was conducted using the Pubmed, Embase, and PsychINFO databases in adherence with the PRISMA guidelines. Results: The search yielded 48 potentially relevant studies, of which 40 were excluded following screening. Eight studies were included in the final review. A total of 97 single nucleotide polymorphisms (SNPs) were examined in the eight included studies. The most prevalent gene was FKBP5, and the best studied polymorphism was FKBP5:rs1360780. Two of the five studies reported significant gene-environment (G x E) interactions between rs1360780 and SLE. Overall, four studies reported significant G x E interactions between FKBP5, CRH, or CRHR1 and SLE, respectively. No significant G x E interactions were found for the remaining genes. Conclusions: Our results suggest that genetic variation in three genes in the HPA-axis possibly moderate the effects of SLEs in depression. Significant Outcomes A systematic literature search identified eight original studies investigating the interaction between genetic variations in eight genes involved in the HPA-axis and SLE in depression. Gene-environment interactions may partly explain why some people react differently to stress than others. Our results suggest that three genes (FKBP5, CRH, and CRHR1) in the HPA-axis possibly moderate the effects of stressful life events in depression. FKBP5 was the most prevalent gene, and rs1360780 was the best studied polymorphism. No gene-environment interactions were found, and little research was available for five other genes involved in the HPA-axis (ACE, AVP, CRHR2, NR3C1, and NR3C2). Limitations Despite following the recommended guidelines for systematic reviews, relevant literature may have been missed. The included gene-environment interaction studies are based on candidate gene studies. This approach is hypothesis-driven, resulting in selection bias. Future research in this field will likely shift from candidate gene interaction studies towards genome-wide environment interaction studies, with a systematic characterisation of multiple environmental factors in large samples.