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Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms: A Genetic Correlation and 2-Sample Mendelian Randomization Study

Nils Kappelmann, Janine Arloth, Marios K Georgakis, Darina Czamara, Nicolas Rost, Symen Ligthart, Golam Khandaker, Elisabeth B Binder, Apollo-University Of Cambridge Repository
Importance Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin (IL)-6, a cytokine stimulating CRP production, with individual depressive symptoms. However, it is unclear whether inflammatory activity causes individual depressive symptoms, and to what extent metabolic dysregulation underlies the reported associations. Objective To explore the genetic overlap and causal relationships between inflammatory activity, metabolic
more » ... tivity, metabolic dysregulation, and individual depressive symptoms. GWAS Data Sources GWAS summary data of European individuals for CRP levels (n=204,402); nine individual depressive symptoms, three of which combined increase/decrease (e.g. sleep), as measured with Patient Health Questionnaire (PHQ)-9 (n=up to 117,907); major depression (MD) including (n=500,199) and not including UK Biobank participants (up to n=230,214); insomnia (up to n=386,533); Body Mass Index (BMI, up to n=322,154); and height (up to n=253,280). Design Genetic correlation and two-sample Mendelian Randomisation (MR) study. We applied Linkage disequilibrium score (LDSC) regression to infer SNP-based heritability and genetic correlation estimates. Two-sample MR testing potential causal associations with depressive symptoms using genetic variants associated with higher CRP levels, IL-6 signalling, and BMI as instruments. Results Genetic correlation analyses revealed consistent false discovery rate (FDR) controlled associations (rg range: 0.152-0.362, all PFDR<0.01) 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 signalling was associated with suicidality (estimate=0.035, standard error [SE]= 0.010, PFDR+Bonferroni=0.011), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. MR analyses did not consistently show associations of higher CRP levels or [...]
doi:10.17863/cam.60144 fatcat:qcvhyx3en5hbhkgbi2mefiwpce