Genetic Contributions of Inflammation to Depression

Abstract

This paper describes the effects of immune genes genetic variants and mRNA expression on depression's risk, severity, and response to antidepressant treatment, through a systematic review on all papers published between 2000 and 2016. Our results, based largely on case-control studies, suggest that common genetic variants and gene-expression pathways are involved in both immune activation and depression. The most replicated and relevant genetic variants include polymorphisms in the genes for interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, C-reactive protein, and phospholipase A2. Moreover, increased blood cytokines mRNA expression (especially of IL-1β) identifies patients that are less likely to respond to conventional antidepressants. However, even for the most replicated findings there are inconsistent results, not only between studies, but also between the immune effects of the genetic variants and the resulting effects on depression. We find evidence that these discrepant findings may be explained, at least in part, by the heterogeneity of the depression immunophenotype, by environmental influences and gene × environment interactions, and by the complex interfacing of genetic variants with gene expression. Indeed, some of the most robust findings have been obtained in patients developing depression in the context of treatment with interferon-alpha, a widely used model to mimic depression in the context of inflammation. Further 'omics' approaches, through GWAS and transcriptomics, will finally shed light on the interaction between immune genes, their expression, and the influence of the environment, in the pathogenesis of depression.

Figure 1

The conflicting needs of an individual according to the environment could explain why some immune genetic variants are still present in the human pool even if they confer risk of both depression and metabolic abnormalities. In a theoretical ancestral setting, ‘at risk' polymorphisms, such as the TNF-α 308A allele, may maintain plasma glucose in the harshest of conditions, allowing cerebral energy load to be maintained in the face of famine, acute stress (such as attack or flight), and infection. This polymorphism may also interact with the mutually reinforcing high-producing IL-6 174 G allele to mount a strong immune response to pathogens, and conserve energy via reduced physical activity during acute infection. Similarly, the MCP1 2518A allele reduces skeletal muscle uptake of glucose, making more energy available to the immune system for infection combat. At the same time, consistently high levels of activity employed in foraging and hunting help to keep the excesses of these polymorphisms in check, aided by the anti-inflammatory actions of the IL-10 1082 ‘protective' G polymorphism. However, in a modern setting, the sedentary lifestyle, the atmosphere of continuous low-level stress, and the tendency toward excess calorie intake, turn these genetic advantages into systemic millstones, creating a downward self-reinforcing, obesogenic, diabetic, pro-atherosclerotic system, whose ultimate result is the metabolic syndrome and cardiac disease.