This genetic correlation and 2-sample mendelian randomization study uses large-scale genome-wide association data sources to explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms.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 (204402 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 386533 individuals); body mass index (BMI) (up to 322154 individuals); and height (up to 253280 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 strategy for suicide prevention.Question Do inflammatory pathways share a genetic background with individual depressive symptoms, and do they potentially causally contribute to them? Findings Based on large genome-wide association study data sources, this genetic correlation and 2-sample mendelian randomization study found genetic overlap between a higher C-reactive protein (CRP) level, a broad marker of inflammation, and 9 depressive symptoms; upregulated interleukin-6 signaling, a major stimulator of CRP, emerged as a potential causal risk factor for suicidality. Body mass index, but not interleukin 6 or CRP, was potentially causally associated with 4 other depressive symptoms. Meaning Interleukin 6 overactivity could be associated with suicidality; interleukin-6 blockade may be a novel treatment target that warrants future research.