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

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: C-reactive protein; Mendelian randomization; blood metabolites; schizophrenia.

Figure 1

Scatter plots of MR analyses using several models to investigate causal relationships between CRP (C-reactive protein) and SCZ (schizophrenia). The four models applied in the current manuscript are all denoted. (A) Forward models assessing the effect of CRP on SCZ liability. Lines in dashed, dotted and dotdash represent β for fixed effect IVW, weighted median, and MR Egger models using 52 instruments. The longdash line is β from GSMR model with 45 instruments removing outlier detected by HEIDI test. The scatters in grey are instrument outliers by HEIDI (Heterogeneity in Dependent Instruments) test. (B) Reverse models assessing the effects of genetic liability to SCZ on CRP. Lines in dashed, dotted and dotdash represent β for fixed effect IVW, weighted median, and MR Egger models using 106 instruments. The longdash line is β from GSMR model with 105 instruments removing outlier detected by HEIDI test. The scatters in blue are instrument outliers by HEIDI (Heterogeneity in Dependent Instruments) test. IVW, inverse variance-weighted model; GSMR, generalized summary-data-based Mendelian-randomization model.

Figure 2.

Diagnostic plot of the best individual MR-BMA model (including Citrate (Cit) and Lactate (Lac)), showing predicted associations with SCZ (fitted β values on SCZ, x-axis) against the observed associations with SCZ (β values from the SCZ summary statistics, y-axis). Each dot represents an instrument variable (n = 129 genetic variants). The color code shows: (A) the Q-statistic for outliers and (B) Cook's distance for influential points. Any genetic variants with Q-statistic > 8 or Cook's distance > 0.03 (4/129) are marked by a label indicating the gene region. One variant was detected as an outlier (with minimum Q-statistic > 10 and minimum Cook's distance > 0.01 in all the models with posterior probability (PP) > 0.01): the intergenic variant rs193084249, denoted as ‘intergenic’ in the graph. (A) the Q-statistic: Cit + Lac. (B) Cook's distance: Cit + Lac. Cit, citrate; Lac, lactate, SCZ, schizophrenia.