Open AccessAssessing causal links between metabolic traits, inflammation and schizophrenia: a univariable and multivariable, bidirectional Mendelian-randomization study
Author(s) -
Bochao Lin,
Anne Alkema,
Triinu Peters,
Janneke Zinkstok,
Lars Libuda,
Johannes Hebebrand,
Jack P. Antel,
Anke Hinney,
Wiepke Cahn,
Roger A.H. Adan,
Jurjen J. Luykx
Publication year - 2019
Publication title -
international journal of epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.406
H-Index - 208
eISSN - 1464-3685
pISSN - 0300-5771
DOI - 10.1093/ije/dyz176
Subject(s) - mendelian randomization , schizophrenia (object oriented programming) , multivariable calculus , causal inference , medicine , randomization , bioinformatics , clinical psychology , psychology , randomized controlled trial , biology , psychiatry , genetics , genetic variants , gene , pathology , genotype , control engineering , engineering
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.