A Comprehensive Atlas of Plasma Metabolites Uncovers Neurological Disease Pathways and Early Metabolic Signatures
Objective:
This study aims to present a comprehensive atlas of plasma metabolites associated with neurological diseases, quantify metabolomic changes prior to disease onset, and elucidate potential causal relationships between metabolites and diseases.
Background:
Plasma metabolites play a crucial role in identifying biomarkers, categorizing diseases, and assessing risks. However, most metabolomic studies have been cross-sectional, often missing early metabolic signatures due to potential reverse causality. Understanding the evolutionary patterns of metabolites in relation to diseases, especially before clinical manifestation, can enhance our understanding of etiology and biological signatures, facilitate personalized risk assessment, and advance precision medicine.
Design/Methods:
We present an extensive atlas comprising 313 nuclear magnetic resonance (NMR)-based plasma metabolic biomarkers linked to 50 neurological diseases, analyzed within a cohort of 274,241 participants. This study represents the largest metabolome profiling to date. A nested case-control study was conducted to delineate the temporal trajectories of neurological diseases 15 years before onset, clustering diseases with similar metabolic patterns. Mendelian randomization was used to explore potential causal relationships, complemented by colocalization analysis to identify shared genetic determinants.
Results:
Our atlas revealed 2,378 associations between metabolites and neurological diseases. Among these associations, 29.3% of the metabolite changes occurred more than a decade before disease onset. Diseases were grouped into 14 clusters based on their temporal trajectories, with 8 clusters comprising more than three diseases. Notably, creatinine, albumin, and acetate emerged as key markers in predicting neurological diseases. Mendelian randomization identified 8 significant metabolite-disease associations and 38 notable disease-driven metabolite alterations, particularly highlighting linoleic acid's potential protective effect against nerve disorders, supported by 103 colocalized SNPs in the colocalization analysis.
Conclusions:
This atlas offers valuable insights into the pathophysiology, diagnosis, prediction, and treatment strategies for neurological diseases. It acts as a comprehensive tool for implementing precision medicine in clinical practice.
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