Article
Mediation-adjusted multivariable Mendelian randomization study identified novel metabolites associated with psychiatric disorders
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Authors
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Dennis Freuer
- Epidemiologie, Medizinische Fakultät Augsburg, Augsburg, Germany
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Christa Meisinger
- Epidemiologie, Medizinische Fakultät Augsburg, Augsburg, Germany
| Published: | September 6, 2024 |
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Outline
Text
Background: From the pathway perspective, metabolites have the potential to improve knowledge about the etiology of psychiatric diseases. Previous studies suggested a link between specific blood metabolites and mental disorders, but some Mendelian randomization (MR) studies in particular are insufficient for various reasons. Thus, this study focused on bias assessment due to interdependencies between metabolites and psychiatric mediation effects.
Methods: For metabolites, summary statistics from a genome-wide association study (GWAS) by Shin et al. were used, investigating 453 different metabolites in human blood and including up to 7824 participants of European ancestry [1]. Data for the diagnosed mental disorders ADHD, anxiety, bipolar disorder, anorexia nervosa, depression, PTSD, schizophrenia, and at least one suicide attempt were obtained from the iPSYCH project and the Psychiatric Genomics Consortium (PGC). The number of cases ranged between 6,024 and 294,322 cases. Replication datasets originated from the FinnGen database with up to 24,662 self-reported cases.
In a multi-step framework containing network and multivariable MR, direct effects of 21 eligible and mutually adjusted metabolites on mental disorders were estimated after identifying and accounting for potential psychiatric mediation mechanisms. Robust inverse-variance weighted models with random effects were used in primary analyses. Several sensitivity analyses were performed to assess different patterns of pleiotropy and weak instrument bias. The pleiotropy-robust approaches included multivariable MR-Egger, Median, Lasso, and adjusted debiased IVW methods. Estimates for the same outcome-phenotypes from different resources were pooled using fixed effect meta-analysis models.
Results: After adjustment for mediation effects, genetically predicted metabolite levels of 6 metabolites of lipid, amino acid, and cofactors pathways were associated with overall 6 mental disorders (ADHD, bipolar disorder, anorexia nervosa, depression, PTSD, and schizophrenia). Point estimates ranged from -0.45 (95% CI: [-0.67; -0.24], P=1∙10-4) to 1.78 (95% CI: [0.85; 2.71], P=0.006). Sensitivity analyses and heterogeneity statistics supported the results.There was no evidence of any association with anxiety and suicide attempt.
Conclusions: In this study, we identified some new blood metabolites that seem to be causally related to certain psychiatric disorders.
The authors declare that they have no competing interests.
The authors declare that an ethics committee vote is not required.
References
- 1.
- Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J, et al. An atlas of genetic influences on human blood metabolites. Nat Genet. 2014;46(6):543-50.
