Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms

Abstract

IMPORTANCE Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin 6 (IL-6), a cytokine-stimulating CRP production, with individual depressive symptoms. However, it is unclear whether inflammatory activity is associated with individual depressive symptoms and to what extent metabolic dysregulation underlies the reported associations. OBJECTIVE To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms. GWAS DATA SOURCES Genome-wide association study (GWAS) summary data of European individuals, including the following: CRP levels (204 402 individuals); 9 individual depressive symptoms (3 of which did not differentiate between underlying diametrically opposite symptoms [eg, insomnia and hypersomnia]) as measured with the Patient Health Questionnaire 9 (up to 117 907 individuals); summary statistics for major depression, including and excluding UK Biobank participants, resulting in sample sizes of 500 199 and up to 230 214 individuals, respectively; insomnia (up to 386 533 individuals); body mass index (BMI) (up to 322 154 individuals); and height (up to 253 280 individuals). DESIGN In this genetic correlation and 2-sample mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer single-nucleotide variant-based heritability and genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with CRP levels, IL-6 signaling, and BMI with depressive symptoms. The study dates were November 2019 to April 2020. RESULTS Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)-controlled associations (genetic correlation range, 0.152-0.362; FDR P = .006 to P < .001) between CRP levels and depressive symptoms that were similar in size to genetic correlations of BMI with depressive symptoms. Two-sample MR analyses suggested that genetic upregulation of IL-6 signaling was associated with suicidality (estimate [SE], 0.035 [0.010]; FDR plus Bonferroni correction P = .01), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. Mendelian randomization analyses did not consistently show associations of higher CRP levels or IL-6 signaling with other depressive symptoms, but higher BMI was associated with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. CONCLUSIONS AND RELEVANCE This study reports coheritability between CRP levels and individual depressive symptoms, which may result from the potentially causal association of metabolic dysregulation with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. The study also found that IL-6 signaling is associated with suicidality. These findings may have clinical implications, highlighting the potential of anti-inflammatory approaches, especially IL-6 blockade, as a putative strate...

Association of Inflammation with Depression and Anxiety: Evidence for Symptom-Specificity and Potential Causality from UK Biobank and NESDA Cohorts

“…We also replicated a previously reported MR association between IL-6 and suicidal ideation (cf. Kappelmann et al [21]), but this association did not survive multiple comparison correction.…”

Polygenic risk for immuno-metabolic markers and specific depressive symptoms: A multi-sample network analysis study

“…For sleep problems and changes in appetite (available in the PHQ-9), only insomnia and loss of appetite are available in the HAM-D, so we included both conflated and unidirectional symptoms in network analyses as previous studies have specifically highlighted associations of inflammation with these symptoms (Jokela et al, 2016; Milaneschi et al, 2017b). We reasoned that comparative appraisal of associations, for example with changes in appetite and loss of appetite, could give further indications on potential specificity of associations to symptom directions, as observed in a previous report (Kappelmann et al, 2020).…”

“…We reasoned that comparative appraisal of associations, for example with changes in appetite and loss of appetite, could give further indications on potential specificity of associations to symptom directions, as observed in a previous report (Kappelmann et al, 2020).…”

“…Evidence from in-depth immunophenotyping further suggests that there may be distinct subgroups of inflammation-related depression as shown by immune cell count clustering and transcriptome analyses (Cattaneo et al, 2020;Lynall et al, 2020). These studies suggest that acutely elevated levels of inflammatory markers are associated with depression, but associations of depression with genetic/lifetime predisposition to higher inflammatory markers has been studied less frequently and primarily for CRP (Badini et al, 2020;Kappelmann et al, 2020;Milaneschi et al, 2017bMilaneschi et al, , 2016. Moreover, inflammatory markers such as CRP are influenced by metabolic factors (Timpson et al, 2011), which may causally underlie some inflammationsymptom associations (Kappelmann et al, 2020), so a combined investigation of immunometabolic factors is needed to disentangle their etiological roles.…”

“…Regarding clinical complexity, studies have shown associations of inflammatory markers with specific depressive symptoms including fatigue, changes in appetite, anhedonia, and suicidality (Badini et al, 2020;Fried et al, 2019;Jokela et al, 2016;Kappelmann et al, 2020;Köhler-Forsberg et al, 2017;Lamers et al, 2020Lamers et al, , 2018Milaneschi et al, 2017a;Moriarity et al, 2020a;Simmons et al, 2018;White et al, 2017). Most prior research, however, has restricted its investigation to complexity on one side, that is focusing on multiple immune markers (e.g., cell counts/ serum cytokine levels) while studying a composite depression phenotype or focusing on multiple depressive symptoms in the context of a single inflammatory marker (mostly CRP).…”