Assessing causal links between metabolic traits, inflammation and schizophrenia: a univariable and multivariable, bidirectional Mendelian-randomization study

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Blood immunoreactive biomarkers, such as C-reactive protein (CRP), and metabolic abnormalities have been associated with schizophrenia. Studies comprehensively and bidirectionally probing possible causal links between such blood constituents and liability to schizophrenia are lacking.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>To disentangle putative causal links between CRP blood levels and schizophrenia in both directions, we conducted multiple univariable Mendelian-randomization (MR) analyses, ranging from fixed-effect to inverse variance-weighted (IVW), weighted-median, MR Egger and generalized summary-data-based Mendelian-randomization (GSMR) models. To prioritize metabolic risk factors for schizophrenia, a novel multivariable approach was applied: multivariable Mendelian-randomization–Bayesian model averaging (MR-BMA).</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>All forward univariable MR analyses consistently showed that CRP has a protective effect on schizophrenia, whereas reverse MR analyses consistently suggested absent causal effects of schizophrenia liability on CRP blood levels. Using MR-BMA, as the top protective factors for schizophrenia we prioritized leucine and as the prime risk-factor triglycerides in medium very-low-density lipoprotein (VLDL). The five best-performing MR-BMA models provided one additional risk factor: triglycerides in large VLDL; and two additional protective factors: citrate and lactate.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our results add to a growing body of literature hinting at metabolic changes—in particular of triglycerides—independently of medication status in schizophrenia. We also highlight the absent effects of genetic liability to schizophrenia on CRP levels.</jats:p> </jats:sec>