1. Coheritability was found between individual depressive symptoms and C-reactive protein (CRP) levels.
2. There may be a causal association of CRP and depression with metabolic dysregulation.
3. Interleukin 6 signaling was associated with suicidality.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Inflammation, C-reactive protein (CRP), and interleukin 6 (IL-6) are implicated in depressive symptoms and suicidal behaviors. Much of what is known about the biological aspects of depression are difficult to translate to clinical practice. The degree to which genetics impact these associations and resulting depressive phenotypes continues to be questioned. This study aimed to determine whether or not there is a shared genetic background between inflammatory pathways in individuals with depressive symptoms.
This genome-wide association study (GWAS) utilized data from Europe with between 117,907 and 500,199 participants, depending on the variable of interest. Findings suggested coheritability between individual depressive symptoms and CRP levels, possibly stemming from the causal association of metabolic dysregulation with feelings of inadequacy, changes in appetite, anhedonia, and fatigue. IL-6, a marker for inflammation, was found to be associated with suicidality, which aligns with suicidal individuals who also present with inflammatory conditions. Suicidal behavior originates from complex sequence of biological events, which are recursive in nature but may harbor the potential for future treatments. Study findings identify possible biomarkers associated with suicidality, and suggest a possible role for anti-inflammatory approaches to treatment as a useful strategy for these populations.
In-Depth [ retrospective cohort]:
This genetic correlation and two-sample mendelian randomization study utilized large-scale GWAS data sources from November 2019 to April 2020. Participant count depended on the variable of interest. Serum CRP levels from 204,402 individuals, 500,199 individuals with depression, 322,154 with body-mass index (BMI), 253,280 with height and soluble IL-6 receptor (sIL-6R) protein levels, 386,533 with insomnia, and 117,907 with completed Patient Health Questionnaires 9 (PHQ-9). Linkage disequilibrium score (LDSC) regression and MR analyses allowed for the dissection of the relationships between metabolic factors, depressive symptoms, and inflammation. The LDSC regression also allows for the assessment of single-nucleotide variants (SNV)-based phenotype heritability (h2) and coheritability between two traits. LDSC was used to estimate h2 and CRP-level genetic correlations between MD, BMI, and height.
SNV-based heritability was low for depressive symptoms (h2 range = 0.0143 to 0.0631), CRP levels (h2 = 0.0941), and MD (h2 range = 0.0599 to 0.0723). However, BMI (h2 = 0.1297) and height (h2 = 0.3120) demonstrated higher levels of heritability. Suicidality h2 was lower than the suggested threshold of z>4, which could potentially reflect unreliability of estimates of genetic correlation. There was evidence for genetic correlation between CRP levels and all depressive symptoms (genetic correlation range = 0.152 to 0.362). BMI-depressive symptom estimates were also associated with CRP-depressive symptom estimates (Pearson r = 0.89, Spearman ρ = 0.92, p = 0.001). MR analyses of CRP levels did not demonstrate associations with depressive symptoms, insomnia, or MD. However, there was some evidence of associations with appetite changes, fatigue, and psychomotor changes, but these could not be replicated in weight median MR. MR analyses were, however, able to observe an association of suicidality with upregulated IL-6 signaling (estimate [SE] = 0.035 [0.010]; FDR plus Bonferroni P = 0.01), but IL-6 signaling was not associated with MD, insomnia, or other depressive symptoms.
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