Dissecting the Association Between Inflammation, Metabolic D
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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. To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms a study was conducted.

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 117907 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).

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.

Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)–controlled associations (genetic correlation range, 0.152-0.362) 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, 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.

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. Regarding proinflammatory processes, IL-6 signaling may be potentially causally associated with suicidality. This hypothesis is clinically relevant because symptom expression of suicidality could help identify patients who will respond to immunotherapy. The findings also suggest that pharmacological approaches targeting IL-6 signaling may be valuable for treatment of suicidality, which requires further research.

Source: https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2771875
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