Prospective epidemiological studies found that generalized anxiety disorder (GAD) can impair immune function and increase risk for cardiovascular disease or events. Mechanisms underlying the physiological reverberations of anxiety, however, are still elusive. Hence, we aimed to investigate molecular processes mediating effects of anxiety on physical health using blood gene expression profiles of 336 community participants (157 anxious and 179 control). We examined genome-wide differential gene expression in anxiety, as well as associations between nine major modules of co-regulated transcripts in blood gene expression and anxiety. No significant differential expression was observed in women, but 631 genes were differentially expressed between anxious and control men at the false discovery rate of 0.1 after controlling for age, body mass index, race, and batch effect. Gene set enrichment analysis (GSEA) revealed that genes with altered expression levels in anxious men were involved in response of various immune cells to vaccination and to acute viral and bacterial infection, and in a metabolic network affecting traits of metabolic syndrome. Further, we found one set of 260 co-regulated genes to be significantly associated with anxiety in men after controlling for the relevant covariates, and demonstrate its equivalence to a component of the stress-related conserved transcriptional response to adversity profile. Taken together, our results suggest potential molecular pathways that can explain negative effects of GAD observed in epidemiological studies. Remarkably, even mild anxiety, which most of our participants had, was associated with observable changes in immune-related gene expression levels. Our findings generate hypotheses and provide incremental insights into molecular mechanisms mediating negative physiological effects of GAD.
Individuals with generalized anxiety disorder (GAD) experience daily excessive, uncontrollable, and often irrational worry (Torpy et al., 2011). GAD is fairly common with a lifetime prevalence of 5.7% (Kessler et al., 2005). Prospective epidemiological studies have found that GAD is a risk factor for cardiovascular diseases and cardiac events over many ensuing years (Dimsdale, 2010, Martens et al., 2010, Janszky et al., 2010 and Roest et al., 2010). For instance, a prospective cohort study following 1015 patients for a mean of 5.6 years found that GAD was associated with a 62% higher rate of cardiovascular events (defined as stroke, transient ischemic attack, heart failure, myocardial infarction, or death) after comorbid conditions, including major depressive disorder, hypertension, history of myocardial infarction, diabetes, congestive heart failure, stroke, cardiac disease severity, medication use, and age have been accounted for (Martens et al., 2010). Another prospective study of 49,000 young Swedish men followed for 37 years found multi-adjusted hazard ratios for coronary heart disease and acute myocardial infarction to be 2.17 and 2.51 respectively for anxious men (Janszky et al., 2010). Interestingly, a variety of potential mediators for the association of GAD and cardiovascular diseases and events have been examined, including C-reactive protein level, heart rate variability, smoking, medication non-adherence, and physical inactivity, but they did not explain the association (Martens et al., 2010). Why anxiety increases risks of cardiovascular disease and events is still poorly understood.
Despite its limitations, this is the first study, to our knowledge, to examine genome-wide differential gene expression in anxiety, and associations between anxiety and the major axes of covariance in blood gene expression. We found that even mild anxiety symptoms were associated with altered gene expression levels related to innate and adaptive immune responses in men more than women. Our findings generate hypotheses for future studies focusing on biological mechanisms underlying physiological reverberations of anxiety disorders.
