Body mass index and inflammation in depression and treatment-resistant depression: a Mendelian randomisation study

Abstract

Background: Major depressive disorder (MDD) has a significant impact on global burden of disease. Complications in clinical management can occur when response to pharmacological modalities is considered inadequate and symptoms persist (treatment-resistant depression (TRD)). We aim to investigate inflammation, proxied by C-reactive protein (CRP) levels, and body mass index (BMI) as putative causal risk factors for depression and subsequent treatment resistance, leveraging genetic information to avoid confounding via Mendelian randomisation (MR).

Methods: We used the European UK Biobank subcohort ([Formula: see text]), the mental health questionnaire (MHQ) and clinical records. For treatment resistance, a previously curated phenotype based on general practitioner (GP) records and prescription data was employed. We applied univariable and multivariable MR models to genetically predict the exposures and assess their causal contribution to a range of depression outcomes. We used a range of univariable, multivariable and mediation MR models techniques to address our research question with maximum rigour. In addition, we developed a novel statistical procedure to apply pleiotropy-robust multivariable MR to one sample data and employed a Bayesian bootstrap procedure to accurately quantify estimate uncertainty in mediation analysis which outperforms standard approaches in sparse binary outcomes. Given the flexibility of the one-sample design, we evaluated age and sex as moderators of the effects.

Results: In univariable MR models, genetically predicted BMI was positively associated with depression outcomes, including MDD ([Formula: see text] ([Formula: see text] CI): 0.133(0.072, 0.205)) and TRD (0.347(0.002, 0.682)), with a larger magnitude in females and with age acting as a moderator of the effect of BMI on severity of depression (0.22(0.050, 0.389)). Multivariable MR analyses suggested an independent causal effect of BMI on TRD not through CRP (0.395(0.004, 0.732)). Our mediation analyses suggested that the effect of CRP on severity of depression was partly mediated by BMI. Individuals with TRD ([Formula: see text]) observationally had higher CRP and BMI compared with individuals with MDD alone and healthy controls.

Discussion: Our work supports the assertion that BMI exerts a causal effect on a range of clinical and questionnaire-based depression phenotypes, with the effect being stronger in females and in younger individuals. We show that this effect is independent of inflammation proxied by CRP levels as the effects of CRP do not persist when jointly estimated with BMI. This is consistent with previous evidence suggesting that overweight contributed to depression even in the absence of any metabolic consequences. It appears that BMI exerts an effect on TRD that persists when we account for BMI influencing MDD.

Keywords: Body mass index; Depression; Mendelian randomisation.

Fig. 1

Methods overview. a Causal diagram (DAG) representing the assumed relationship between genetic variants for CRP ($G_{\mathit{CRP}}$), measured levels of serum CRP and BMI, and major depressive disorder (MDD). The dashed line between CRP and BMI represents a potential contribution of BMI to CRP levels. b DAG for an MVMR analysis that genetically proxies both CRP and BMI ($G_{\mathit{CRP}},G_{\mathit{BMI}}$) enables estimation of the direct causal effect of CRP and BMI on MDD. c Estimation of the proportion of the CRP effect mediated by BMI (p${}_m$). d Robust MVMR to account for unmeasured pleiotropy as well as measured BMI pleiotropy. If some of the genetic variants in $G_{\mathit{CRP}}$ or $G_{\mathit{BMI}}$ affect MDD directly, other than just through changing CRP or BMI levels, the estimated effects will be biased. Robust methods such as MR GRAPPLE protect against this

Fig. 2

Effects of BMI and CRP on various depression-related outcomes as measured by univariable and multivariable MR models. The CRP effect is measured by using 45 CRP SNPs as instruments. UV, univariable MR; MV, multivariable MR; GRAPPLE, robust multivariable MR with MR GRAPPLE; CIDI, Composite International Diagnostic Interview; PHQ9, Patient Health Questionnaire-9; TRD, treatment-resistant depression

Fig. 3

Proportion of CRP effect mediated by BMI, defining the CRP effect with two different instruments (45 CRP SNPs, rs2794520 (C $\to$ T)) in the CRP region). Two methods of bootstrapping are used to estimate the uncertainty (Bayesian bootstrap, non-parametric bootstrap). CIDI, Composite International Diagnostic Interview; MDD, major depressive disorder; PHQ9, Patient Health Questionnaire-9; TRD, treatment-resistant depression

Fig. 4

Forest plot for the effect estimates of favourable and unfavourable adiposity and CRP on depression outcomes. CIDI, Composite International Diagnostic Interview; MDD, major depressive disorder; PHQ9, Patient Health Questionnaire-9; TRD, treatment-resistant depression