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

Masatoshi Inoshita,Hiroshi Yoneda,Nakao Iwata,Issei Imoto,Hidenaga Yamamori,Masashi Ikeda,Makoto Kinoshita,Masahito Nakataki,Shusuke Numata,Hidehiro Umehara,Atsushi Tajima,Tetsufumi Kanazawa,Shinji Shimodera,Souichiro Maruyama,Ryota Hashimoto,Tetsuro Ohmori

doi:10.1038/srep26105

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.

Highlights

RETRACTED on the causal pathway between the genotype and the outcome
We examined the association between natural log-transformed serum CRP levels and each single-nucleotide polymorphisms (SNPs) in the non-psychiatric Japanese control subjects (N = 932) using a multiple linear regression analysis with adjustments for age and sex, and calculated a beta coefficient value for each SNP, which represents the number of standard deviation (SD) differences in the natural log-transformed serum CRP levels per the C allele of rs2794520 or the G allele of rs1183910, as done in previous studies[30,31]
On the other hand, when we calculated the effect of the CRP levels on the risk of schizophrenia in the world-wide population by combining 2 pooled estimates, Odds ratio (OR) of schizophrenia from a meta-analysis of GWAS43 and beta of CRP from a meta-analysis of GWAS31, we found a significant effect of CRP levels on schizophrenia, representing an ORscz/cro of 1.15 using rs2794526 and 1.21 using rs1183910, as well as an ORscz/cro of 1.17 across these 2 SNPs (Fig. 3)

Summary

Introduction

RETRACTED on the causal pathway between the genotype and the outcome. By combining the results of the genotype-risk factor association (in this case, genotype-CRP levels) and the genotype-outcome association (in this case, genotype-schizophrenia), one can produce an estimate of the risk factor-outcome association (in this case, CRP levels-schizophrenia) that is free from confounding factors[34]. We tested the hypothesis that CRP itself may play a causal role in the development of schizophrenia. For this purpose, we first investigated whether serum CRP levels were higher in patients with schizophrenia than in non-psychiatric controls by conducting an analysis of covariance (ANCOVA) on a large Japanese cohort (N = 1,337). We conducted a meta-analysis of case-control studies between serum CRP levels and schizophrenia (N = 4,826). We investigated the causal relationship between CRP levels and schizophrenia with a Mendelian randomization approach in the Japanese population and in the world-wide population using 2 single-nucleotide polymorphisms (SNPs) (rs2794520 and rs1183910) as instrumental variables

Methods

Results

Conclusion