A Mendelian Randomization Study Suggests a Role for Inflammation and Metabolic Dysregulation in Suicidality and Depression

depression, suicide, isolation, tired
This study looks at whether inflammatory pathways share a genetic background with individual depressive symptoms and if they may potentially causally contribute to them.

An important marker for inflammation, C reactive protein (CRP) was found to be associated with symptoms of depression, indicating a potential causal role for inflammation and suicidality. These findings, from a Mendelian randomization study, were published in JAMA Psychiatry.

Researchers from the Max Planck Institute of Psychiatry performed a genome-wide association study using data from 500,199 samples from 230,214 participants. Some individuals were assessed for CRP concentrations, for demographics, and by the Patient Health Questionnaire 9 (PHQ-9). All diagnoses were defined by the Diagnostic and Statistical Manual of Mental Disorders-IV.

The investigators estimated a low heritability rates for depressive symptoms (h2 range, 0.0143-0.0631), major depression (h2 range, 0.0599-0.0723), and plasma CRP concentration (h2, 0.0941).

Despite the low heritability estimate of CRP, some evidence of a genetic correlation between CRP levels and all depressive symptoms (genetic correlation range, 0.152-0.362) were observed, in which depressed mood had the lowest correlation (genetic correlation, 0.152; standard error [SE], 0.056; false discovery rate [FDR] P =.006) and appetite alteration the highest (genetic correlation, 0.362; SE, 0.067; FDR P <.001).

The upregulation of interleukin 6 (IL-6) was significantly associated with suicidality (estimate, 0.035; SE, 0.010; FDR with Bonferroni P =.01) but not major depression, depressive symptoms, or insomnia.

The association of IL-6 and suicidality was replicated by the main IL-6 signaling weighted median estimate (P =.006), alternative IL-6 signaling estimate (P =.005), and the alternative IL-6 signaling weighted median estimate (P =.047).

Increased body mass index was associated with anhedonia (estimate, 0.046; SE, 0.012; FDR P =.001), tiredness (estimate, 0.049; SE, 0.018; FDR P =.02), appetite alterations (estimate, 0.121; SE, 0.013; FDR P <.001), and feelings of inadequacy (estimate, 0.028; SE, 0.011; FDR P =.02). After weighting, all estimates remained significant except for feelings of inadequacy.

These results remained robust with a sensitivity analysis, which should have corrected for pleiotropic single nucleotide variants.

This study may have been limited by the granular differences among depressive symptoms which are not differentiated in the PHQ-9 and may have introduced some ambiguity.

The study authors concluded that increased inflammation and metabolic dysregulation may be associated with some symptoms of depression. IL-6 signaling may be an effective tool for stratifying patients at increased risk for suicidality and a potential target for therapeutics treating depressive symptoms. However, future studies are needed to more robustly relate IL-6 activity with suicidal ideation.


Kappelmann N, Arloth J, Georgakis M K, et al. Dissecting the association between inflammation, metabolic dysregulation, and specific depressive symptoms. A genetic correlation and 2-sample Mendelian randomization study. JAMA Psychiatry. 2020;e203436. doi: 10.1001/jamapsychiatry.2020.3436