Significance of risk polymorphisms for depression depends on stress exposure

Abstract

Depression is a polygenic and multifactorial disorder where environmental effects exert a significant impact, yet most genetic studies do not consider the effect of stressors which may be one reason for the lack of replicable results in candidate gene studies, GWAS and between human studies and animal models. Relevance of functional polymorphisms in seven candidate genes previously implicated in animal and human studies on a depression-related phenotype given various recent stress exposure levels was assessed with Bayesian relevance analysis in 1682 subjects. This Bayesian analysis indicated a gene-environment interaction whose significance was also tested with a traditional multivariate analysis using general linear models. The investigated genetic factors were only relevant in the moderate and/or high stress exposure groups. Rank order of genes was GALR2 > BDNF > P2RX7 > HTR1A > SLC6A4 > CB1 > HTR2A, with strong relevance for the first four. Robust gene-gene-environment interaction was found between BDNF and HTR1A. Gene-environment interaction effect was confirmed, namely no main effect of genes, but a significant modulatory effect on environment-induced development of depression were found. Our data support the strong causative role of the environment modified by genetic factors, similar to animal models. Gene-environment interactions point to epigenetic factors associated with risk SNPs. Galanin-2 receptor, BDNF and X-type purin-7 receptor could be drug targets for new antidepressants.

Shared risk alleles with discordant polygenic effects: Disentangling the genetic overlap between ASD and ADHD

“…household income, neighbourhood SES). This is consistent with findings of stress-related gene modulatory effects manifesting, for example, as an environment-induced development of depression 41 .…”

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

“…Several genetic interactions of rs6295 with risk alleles, such as 5-HTTLPR, 65 HTR2A rs6311, or BDNF rs6265 SNPs in major depression, have been reported. 66 The HTR1A rs6295 polymorphism showed strong interaction with life stress and BDNF rs6265 (Val66Met) for major depression 67 and for treatment-resistant depression. 68 The BDNF Val66Met has the highest level of functionality (class 3 69 ), having been shown to phenocopy reduced BDNF trafficking and secretion in a mouse knockin model.…”

“…144 Thus, genotype and stress-induced DNA methylation may interact at specific risk gene promoters to predispose people to major depression. 67 Stress × HTR1A genotype interaction Like 5-HTTLPR, there is evidence that the HTR1A promoter polymorphism interacts with stress for susceptibility to anxiety-and depression-related phenotypes. For example, life separation events interacted with both 5-HTTLPR and HTR1A rs6295 polymorphisms in panic disorder.…”

Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets

“…Physiological effects of IL‐6 polymorphisms depend on its form and location: those in promoter regions that promote IL‐6 expression can increase susceptibility to develop MDD (Bull et al, ) and late‐onset AD (Licastro et al, ), while those that reduce its activity may provide protection against AD (Papassotiropoulos et al, ). Allelic variations in chemokines, cytokines, neuropeptide receptors, and other inflammatory mediators are noted in meta‐analysis studies to influence susceptibilities to either disorder (Bufalino, Hepgul, Aguglia, & Pariante, ; Davis et al, ; Gonda et al, ). Moreover, polymorphisms in gene networks associated with Th1 inflammatory responses both increased the risk for a diagnosis of MDD and predicted responses to 5‐HT (serotonin) reuptake inhibitor (SSRI) antidepressant therapy (Wong, Dong, Maestre‐Mesa, & Licinio, ).…”

“…Most notably, polymorphisms in the promoter region of the IL-1β gene can increase the risk to develop MDD, as well as AD(McCulley, Day, & Holmes, 2003;Murphy et al, 2001;Payao et al, 2012). Physiological effects of IL-6 polymorphisms depend on its form and location: those in promoter regions that promote IL-6 expression can increase susceptibility to develop MDD(Bull et al, 2008) and lateonset AD(Licastro et al, 2003), while those that reduce its activity may provide protection against AD(Papassotiropoulos et al, 2001).Allelic variations in chemokines, cytokines, neuropeptide receptors, and other inflammatory mediators are noted in meta-analysis studies to influence susceptibilities to either disorder(Bufalino, Hepgul, Aguglia, & Pariante, 2013;Davis et al, 2018;Gonda et al, 2018).Moreover, polymorphisms in gene networks associated with Th1inflammatory responses both increased the risk for a diagnosis of MDD and predicted responses to 5-HT (serotonin) reuptake inhibitor (SSRI) antidepressant therapy(Wong, Dong, Maestre-Mesa, & Licinio, 2008). Although accumulating evidence reveals genetic susceptibilities to AD and MDD can be harboured in immune-related genes, a genetic correlation study from genome-wide association meta-analyses statistics did not find statistically significant genetic correlations between the two disorders(Bulik-Sullivan et al, 2015).…”