Associations of inflammatory protein levels and genetic variants with measures of affect and cognitive function in the Dutch Lifelines cohort.

Depression is characterized by an early onset, recurrent course, and high prevalence – all factors contributing to its severe disease burden.1-3 Although the cardinal symptoms of depression are low mood, anhedonia and fatigue,4 it is typically accompanied by a wide range of symptoms, including cognitive dysfunction. Although depressed individuals consistently demonstrate a general pattern of cognitive dysfunction,5 which is observable at first onset of depression,6, 7 for many depressed individuals, cognitive dysfunction persists when depression is in remission.5, 8 The association between cognitive dysfunction and depression is poorly understood.   

The relationship between cognitive functioning and depression may be characterized in four ways. First, cognitive dysfunction may be caused by the presence of depressive symptoms, with cognitive dysfunction limited to the duration of a depressive episode.9 Second, depression, particularly a more severe and/or chronic course, may lead to neuropsychological scarring, such that cognitive dysfunction persists beyond a depressive episode.10 Third, cognitive dysfunction may play a causal role in the onset of depression11-14 – for example, cognitive dysfunction may generate stressful life events (e.g., academic failure) precipitating a depressive episode. Finally, depression and cognitive functioning may not be causally related and, instead, observed associations may be due to common underlying causes.15-17 There is convergent evidence that multiple risk factors (e.g., substance use, sedentary behavior, adiposity, inflammation, and exposure to life stress) are common to both depression18-23 and cognitive dysfunction.24-30 

There is accumulating evidence linking inflammation with both depression31-33 and impaired cognition in people with physical and psychiatric disorders34-36 and in general population samples.29, 37-39 Moreover, chronic inflammation disrupts neuronal processes (e.g., synaptic plasticity/neurogenesis/neurotransmission) and affects brain regions and their respective cognitive associates (e.g., hippocampus: episodic memory; dorsolateral prefrontal cortex/anterior cingulate cortex: executive function) – thereby linking inflammation with abnormal brain structure and function associated with both depression and cognitive dysfunction.40, 41 The causal relationships linking inflammation, depression, and cognitive dysfunction is poorly understood and virtually no data exist testing whether genetic variants may be responsible for the occurrence of cognitive dysfunction in depression. Emerging evidence from genetic approaches, especially Mendelian randomization analysis, suggest a potentially causal role for inflammatory markers (especially IL-6 and CRP) in depression.42-45 However, it is unclear whether inflammation is associated with cognitive dysfunction, and whether these associations are likely to be causal or explained by residual confounding or reverse causality.

In addition to depression, considerable theoretical and empirical evidence suggest that inflammation may be associated with negative affect, such as anxiety, and neuroticism more broadly.46, 47 Stress, whether naturally occurring or experimentally induced, can lead to increased levels of inflammatory proteins in blood and in tissue.48 It is hypothesized that perceived stress can lead to immune system activation via a class of pattern recognition receptors (danger-associated molecular pattern receptors) that are designed to detect cellular stress and tissue damage.49 It is hypothesized that individuals predisposed towards negative affect and/or who experience high levels of anxiety are particularly susceptible to greater levels of stress, which in turn leads to stress-induced increases in inflammation.31, 48, 50 However, less is known about the degree to which inflammation is implicated in depression specifically or negative affect more broadly. Consequently, we also will examine whether the hypothesized associations of inflammatory markers with depression are specific to depression or whether they are linked with negative affect more generally (e.g., depression, anxiety, neuroticism). 

Using data from the LifeLines cohort, we propose to examine whether inflammation, particularly CRP levels, is associated with depression and cognitive dysfunction. Second, we will carry out Mendelian randomization (MR) analysis using genetic variants regulating levels and activity of CRP and IL-6 to test whether associations of inflammation with depression and cognitive dysfunction is likely to be causal or explained by reverse causality or residual confounding. MR is an epidemiological approach that uses genetic variants as instruments to untangle the problem of unmeasured confounding as genetic variants are randomly inherited from parents to offspring and fixed at conception.51 Therefore, if genetically-predicted values of a risk factor are associated with a disease outcome, then it is likely the association between the risk factor and outcome has a causal basis. Finally, we will test whether hypothesized associations of inflammatory markers with depression at baseline are specific to depression or also are observed for negative affect more generally (e.g., anxiety, depression, neuroticism).