ABSTRACT
Background About every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis.
Methods This study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-α, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n=110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n=1,058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n=1,143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three consistency criteria were defined to appraise robustness and replicability of results across estimation methods, network bootstrapping, and samples.
Results Network analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our consistency criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria.
Four additional associations fulfilled at least two consistency criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF-α PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods.
Conclusions Genetic predisposition to higher systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue, consistent with previous studies based on circulating levels of inflammatory markers. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This study is funded by the Max Planck Institute of Psychiatry. NK, NR, and SM are supported by the International Max Planck Research School of Translational Psychiatry (IMPRS-TP). NR received funding from the Bavarian Ministry of Economic Affairs, Regional Development and Energy (BayMED, PBN_MED-1711-0003). GMK acknowledges funding support from the Wellcome Trust (grant code: 201486/Z/16/Z), the MQ: Transforming Mental Health (grant code: MQDS17/40), the Medical Research Council, UK (grant code: MC_PC_17213 and grant code: MR/S037675/1), and the BMA Foundation (J Moulton grant 2019). JA received support by a NARSAD Young Investigator Grant from Brain and Behavior Research Foundation.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
We report secondary analyses for data from existing studies. These studies have received ethics committee approval, which we have described as follows in the manuscript: "MARS received local ethics approval from Ludwig Maximilians University Munich (Hennings et al., 2009). STAR*D received ethics approval from 14 participating institutional review boards, a National Coordinating Center, a Data Coordinating Center, and the Data Safety and Monitoring Board at the National Institute of Mental Health (Rush et al., 2006, 2004). The UK Biobank study received ethics approval from North West Centre for Research Ethics Committee and Human Tissue Authority research tissue bank (Bycroft et al., 2018); this project was approved under project no. 26999. All three studies collected informed consent from participants prior to study participation."
All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.
Yes
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Footnotes
↵* joint senior authors
Revised manuscript, abstract, supplementary material, and figure 1.
Data Availability
Data from original studies is not openly available, but can be requested; see details in Supplementary Table 7. GWAS summary data for IL-6, IL-10, and TNF-α is openly available from the original publication by Ahola-Olli and colleagues (2017), for BMI from the GIANT consortium, and can be requested for CRP from the CHARGE inflammation working group. We provide analysis scripts and estimated network matrices (including bootstrapped network matrices) on the Open Science Platform (OSF) under https://osf.io/q4vw9/.