Summary
This two-sample mendelian randomization study leveraged genetic variants as instrumental variables to investigate whether inflammatory biomarkers causally influence schizophrenia risk, addressing limitations of conventional observational studies prone to reverse causation and confounding. Using summary association results from large consortia with gene-inflammatory biomarker associations estimated in pooled samples up to 80,000 individuals and gene-schizophrenia associations in over 75,000 participants, the authors examined three inflammatory markers: C-reactive protein, interleukin-1 receptor antagonist, and soluble interleukin-6 receptor. Results suggested a protective association between genetically elevated C-reactive protein and schizophrenia risk (pooled OR 0.90 per 2-fold increment, 95% CI 0.84–0.97), contrary to observational findings, with consistent estimates across different mendelian randomization methods.
UK applicability
The findings are relevant to UK psychiatric and public health research, as the study populations were predominantly of European ancestry, which aligns with UK demographics. However, the causal conclusions challenge observational associations previously reported in European populations, suggesting that inflammatory markers alone may not be direct drivers of schizophrenia risk and that UK clinical practice should not prioritise inflammation reduction specifically as a schizophrenia prevention strategy based on this evidence.
Key measures
Pooled odds ratio estimates per 2-fold increment in inflammatory biomarker levels; genetic instruments (18 CRP instruments used); schizophrenia cases (>30,000) and controls (>45,000)
Outcomes reported
The study evaluated whether genetically elevated circulating levels of inflammatory biomarkers (C-reactive protein, interleukin-1 receptor antagonist, and soluble interleukin-6 receptor) causally influence the risk of developing schizophrenia. Risk of schizophrenia was measured as the primary outcome across pooled genetic consortia data.
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