Causal Associations of Cerebrospinal Fluid and Circulating Metabolites With Malignant Brain Neoplasms - Mendelian Randomization Analysis

Sep 23, 2026

Emerging immunometabolism insights highlight metabolic–immune interactions in brain tumor microenvironments, yet causal links between circulating metabolites, cerebrospinal fluid (CSF) metabolites, and malignant brain neoplasms remain unresolved. This Mendelian randomization study used metabolite exposure data from European cohorts for 233 plasma metabolites and 338 CSF metabolites, integrating FinnGen GWAS for malignant brain neoplasms (1070 cases, 345,118 controls) and applying multiple MR approaches plus pathway enrichment.

LanguageEnglish

CategoryHealthcare

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Reading Time28 min

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Abstract

Introduction

Background and clinical burden

Metabolomics and rationale for MR

Brain and Behavior ORIGINAL ARTICLE Causal Associations of Cerebrospinal Fluid and Circulating Metabolites With Malignant Brain Neoplasms: A Mendelian Randomization Analysis Xinyin Zhang1, 2 Zhicheng Wu3 Jing Tan4 Mengting Hu1 Feixia Pan1, 2 Ting Tao1, 2, 5, 6 1National Clinical Research Center for Children and Adolescents’ Health and Diseases, Children’s Hospital Zhejiang University School of Medicine, Hangzhou, China 2Zhejiang Key Laboratory of Neonatal Diseases, Hangzhou, China 3 Department of Environmental Health and Engineering, Johns Hopkins University, Baltimore, Maryland, USA 4 Department of Clinical Laboratory, Children’s Hospital Zhejiang University School of Medicine, Hangzhou, China 5 Department of Surgical Oncology, Children’s Hospital Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents’ Health and Diseases, Hangzhou, China 6 Cancer Center, Zhejiang University, Hangzhou, China Correspondence: Feixia Pan ([21418111@zju.edu.cn](21418111@zju.edu.cn)) Ting Tao (taot@zju.edu.cn) Received: 8 June 2025 Revised: 23 January 2026 Accepted: 25 February 2026 Keywords: brain tumor | cerebrospinal fluid | genome-wide association study | Mendelian randomization | metabolites ABSTRACT Background: Emerging insights from immunometabolism underscore the importance of metabolic–immune interactions in shaping the brain tumor microenvironment and potentially influencing brain behavior and neurological outcomes. Although previous studies have suggested potential links between metabolites and risks of malignant brain tumor development, the causal relationship remains unclarified. Methods: Exposures were extracted from 136,016 Europeans for 233 circulating metabolites and from 689 participants for 338 cerebrospinal fluid (CSF) metabolite levels. Genome-wide association study (GWAS) data for malignant neoplasm of the brain (NCase = 1070, NControl = 345,118) from the FinnGen consortium were used. The primary univariable Mendelian randomization (UVMR) analysis used inverse variance weighting (IVW) and three additional methods for causal assessment. Multivariable MR (MVMR) assessed the direct effects of metabolites, and suggestive biomarkers underwent metabolic pathway enrichment. Results: Twelve metabolic pathways and 21 metabolites (4 circulating biomarkers and 17 CSF metabolites) potentially linked to brain malignancy. The strongest associations were observed for the ratio of omega-3 fatty acids to total fatty acids (IVW: p = 0.01, OR: 0.74, 95% CI: 0.58–0.94) and 5-methylthioadenosine (IVW: p = 0.001, OR: 1.25, 95% CI: 1.09–1.44) . Sensitivity analyses confirmed result robustness. MVMR analysis demonstrated direct effects of blood albumin, along with CSF metabolites such as alpha-hydroxyisocaproate, 1-ribosyl-imidazoleacetate, 5-methylthioadenosine, N1-methylinosine, and urate, independent of other factors. Conclusions: This study reveals metabolite–brain tumor links, shows biomarker potential for screening and prevention, and offers new oncology insights for mechanisms and therapies. | Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; GBM, glioblastoma multiforme; GWAS, genome-wide association study; IVs, instrumental variables; IVW, inverse variance weighting; LD, linkage disequilibrium; MR-Egger, MR-Egger regression; MR-PRESSO, MR Pleiotropy RESidual Sum and Outlier; MTA, 5-Methylthioadenosine; MVMR, multivariable MR; MWAS, metabolome-wide association study; SNPs, single nucleotide polymorphisms; UVMR, univariable Mendelian randomization .
| | --- | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2026 The Author(s). Brain and Behavior published by Wiley Periodicals LLC. | Brain and Behavior, 2026; 16:e71319 1 of 11 [https://doi.org/10.1002/brb3.71319](https://doi.

FAQs

What was the main goal of this Mendelian randomization analysis?

To determine causal associations between cerebrospinal fluid and circulating metabolites and malignant brain neoplasms using genetic instruments rather than observational correlations.

Which datasets and study sizes were used for metabolite exposures and outcomes?

Plasma exposures were derived from 136,016 Europeans for 233 metabolites, CSF exposures from 689 participants for 338 CSF metabolite levels, and outcomes used FinnGen GWAS with 1,070 cases and 345,118 controls.

What kinds of results were reported as potentially linked to brain malignancy?

The study identified 12 metabolic pathways and 21 metabolites potentially associated with brain malignancy, including stronger signals for omega-3 to total fatty acids and 5-methylthioadenosine, with robustness supported by sensitivity analyses.

Sep 23, 2026

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