Inflammatory Biomarkers and Risk of Schizophrenia. A 2-Sample Mendelian Randomization Study

Inflammatory Biomarkers and Risk of Schizophrenia. A 2-Sample Mendelian Randomization Study. Fernando Pires Hartwig et al. JAMA Psychiatry, doi:10.1001/jamapsychiatry.2017.3191

Key Points

Question  What is the effect of increased inflammatory biomarkers on the risk of developing schizophrenia?

Findings  In this 2-sample mendelian randomization study using summary gene-biomarker association results estimated in pooled samples ranging from 1645 to more than 80 000 individuals, 2-fold increments in circulating levels of C-reactive protein and soluble interleukin-1 receptor levels were associated with a 10% reduction and a 6% increase in the lifetime odds of developing schizophrenia.

Meaning  We found that blockade of interleukin-6 effects and low C-reactive protein levels might increase schizophrenia risk, possibly due to increased susceptibility to early life infection.

Abstract

Importance  Positive associations between inflammatory biomarkers and risk of psychiatric disorders, including schizophrenia, have been reported in observational studies. However, conventional observational studies are prone to bias, such as reverse causation and residual confounding, thus limiting our understanding of the effect (if any) of inflammatory biomarkers on schizophrenia risk.

Objective  To evaluate whether inflammatory biomarkers have an effect on the risk of developing schizophrenia.

Design, Setting, and Participants  Two-sample mendelian randomization study using genetic variants associated with inflammatory biomarkers as instrumental variables to improve inference. Summary association results from large consortia of candidate gene or genome-wide association studies, including several epidemiologic studies with different designs, were used. Gene-inflammatory biomarker associations were estimated in pooled samples ranging from 1645 to more than 80 000 individuals, while gene-schizophrenia associations were estimated in more than 30 000 cases and more than 45 000 ancestry-matched controls. In most studies included in the consortia, participants were of European ancestry, and the prevalence of men was approximately 50%. All studies were conducted in adults, with a wide age range (18 to >80 years).

Exposures  Genetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R).

Main Outcomes and Measures  Risk of developing schizophrenia. Individuals with schizophrenia or schizoaffective disorders were included as cases. Given that many studies contributed to the analyses, different diagnostic procedures were used.

Results  The pooled odds ratio estimate using 18 CRP genetic instruments was 0.90 (random effects 95% CI, 0.84-0.97; P = .005) per 2-fold increment in CRP levels; consistent results were obtained using different mendelian randomization methods and a more conservative set of instruments. The odds ratio for sIL-6R was 1.06 (95% CI, 1.01-1.12; P = .02) per 2-fold increment. Estimates for IL-1Ra were inconsistent among instruments, and pooled estimates were imprecise and centered on the null.

Conclusions and Relevance  Under mendelian randomization assumptions, our findings suggest a protective effect of CRP and a risk-increasing effect of sIL-6R (potentially mediated at least in part by CRP) on schizophrenia risk. It is possible that such effects are a result of increased susceptibility to early life infection.