Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

Abstract

BackgroundThe inflammatory markers C-reactive protein (CRP), interleukin-1 receptor antagonist (IL1-Ra), and interleukin-6 (IL-6) have been associated with depression risk in observational studies. The causal nature of these associations is unclear as conventional observational designs are susceptible to reverse causation and residual confounding. Bidirectional Mendelian randomization (MR) analysis uses genetic variants to proxy for risk factors to help elucidate the presence, magnitude, and direction of causal relationships between traits.MethodsWe performed bidirectional two-sample MR to examine causal associations between circulating CRP, IL1-Ra, and IL-6 and major depressive disorder (MDD) in 135,458 cases and 344,901 controls in the Psychiatric Genetics Consortium. Genetic instruments to proxy inflammatory markers and liability to MDD were constructed by obtaining single-nucleotide polymorphisms (SNPs) associated with these phenotypes in genome-wide association study meta-analyses. Wald ratios and inverse-variance weighted random-effects models were employed to generate causal effect estimates and various sensitivity analyses were performed to examine violations of MR assumptions.ResultsThere was evidence supporting a causal effect of circulating IL-6 on risk of MDD (per natural-log increase: OR 0.85, 95% CI: 0.75-0.96, P=0.007). Higher circulating levels of IL-6 as influenced by variants in the IL6R gene region represent lower cellular binding of IL-6 to its receptor and therefore the present results suggest that IL-6 increases the risk of MDD. We found limited evidence supporting a causal effect of CRP (1.06, 95% CI 0.93-1.22; P=0.36) or IL1-Ra (OR 0.95, 95% CI: 0.87-1.03, P=0.20) on risk of MDD. Reverse direction MR analyses suggested limited evidence for a causal effect of genetic liability to MDD on any of the inflammatory markers examined.ConclusionsThese findings support a causal role of IL-6-related pathways in development of major depressive disorder and suggest the possible efficacy of interleukin-6 inhibition as a therapeutic target for depression.

Is the Association Between Smoking and Depression Mediated by Inflammation? A Mendelian Randomization Study

“…Our results did not support a potentially causal relationship between CRP and depression or vice versa , though several observational studies have demonstrated that patients with depression have significantly higher CRP levels when compared to those without depression 26,31,72–75 . Of previously published MR studies assessing this relationship 20,25,26 , our prior study (Khandaker et al (2020)) found evidence for a potentially causal association between CRP levels and depression using data from the UK Biobank cohort. More recently, using the MR approach Kappelmann and colleagues have reported that inflammatory markers like CRP and IL-6 are associated with specific symptoms of depression, such as suicidality 76 .…”

“…Previous studies have shown through MR analyses that smoking and depression may have a bidirectional causal relationship 24 , although the mechanism through which smoking causes depression is not known. MR studies using CRP as a proxy for systemic inflammation have shown conflicting evidence regarding the association between higher CRP levels and risk for depression 20,25,26 . Recently, statistically better powered genome wide association studies (GWAS) for depression 27 and for CRP 28 have become available, and provide an opportunity to use improved genetic instruments, which explain a larger proportion of the variable’s variance, for causal inference to resolve prior ambiguities.…”

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis

“…Indeed, inflammation in general is a known contributor to depression, 8 and a recent study found evidence for interleukin-6 playing a causal role on MDD risk. 9 Interleukin-6 is an inflammatory marker whose levels are also elevated in MS. 32…”

“…In the reverse direction, inflammation is a known contributor to MDD (at least in a subset), 8 and a recent MR study found evidence for interleukin-6 playing a causal role on MDD risk, while bidirectional analyses suggested a limited role for a causal effect of genetic liability to MDD on interleukin-6 and other inflammatory markers (C-reactive protein, interleukin-1 receptor antagonist). 9…”

Socially stratified DNA-methylation profiles are associated with disparities in child and adolescent mental health

“…While inflammation is an essential component of immunosurveillance and host defense, a chronic low-grade inflammatory state is a pathological feature of a wide range of chronic health conditions that is also known to affect brain and psychological development 9,10 . Second, we examined genetic profiles of inflammation (i.e., polygenic scores of CRP, PGS-CRP 11 ), because there are genetic correlations of CRP with mood disorders in adults, such as PTSD 12 and depressive symptoms 13 that may include causal effects of CRP on depression 14,15 . Third, we previously reported that socioeconomic disadvantage and Latinx compared to White identity is associated with the pace of multi-system biological aging, as indicated by DunedinPoAm 16 , in an earlier sub-sample of salivary DNA-methylation data from the Texas Twin Project (N=600) 17 .…”