A significant causal association between C-reactive protein levels and schizophrenia

Abstract

Many observational studies have shown elevated blood CRP levels in schizophrenia compared with controls, and one population-based prospective study has reported that elevated plasma CRP levels were associated with late- and very-late-onset schizophrenia. Furthermore, several clinical studies have reported the efficacy of anti-inflammatory drugs on the symptoms in patients with schizophrenia. However, whether elevated CRP levels are causally related to schizophrenia is not still established because of confounding factors and reverse causality. In the present study, we demonstrated that serum CRP levels were significantly higher in patients with schizophrenia than in the controls by conducting a case-control study and a meta-analysis of case-control studies between schizophrenia and serum CRP levels. Furthermore, we provided evidence for a causal association between elevated CRP levels and increased schizophrenia risk by conducting a Mendelian randomization analysis. Our findings suggest that elevated CRP itself may be a causal risk factor for schizophrenia.

Figure 1. Differences in the serum CRP levels between patients with schizophrenia and controls separately by genotypes (rs2794520 and rs1183910).

The ANCOVA demonstrated that the serum CRP levels in patients with schizophrenia were significantly higher than in controls in most of the strata after the Bonferroni adjustment (*age and gender-adjusted p < 0.05).

Figure 2. Meta-analyses of case-control studies between serum CRP levels and schizophrenia.

The results of the meta-analysis of fifteen case-control studies which measured serum CRP levels (N = 4,734). The serum CRP levels were significantly higher in patients with schizophrenia than in the controls (SMD = 0.62; 95% CI, 0.24–0.99; p = 1.4 × 10⁻³ in the random-effects model).

Figure 3. Mendelian randomization analysis.

Both a Mendelian randomization estimate based on each SNP (rs2794520 and rs1183910) and a pooled Mendelian randomization estimate across these 2 SNPs showed significant effects of CRP levels on schizophrenia risk (p = 0.046, p = 0.014, and p = 0.0017, respectively).