What question did this study set out to answer?

The aim is to explore the causal effects of plasma metabolites on different types of anxiety disorders using Mendelian randomization.

March 31, 2026Open Access

Anxiety Disorder Types From a Metabolomics Perspective: A Mendelian Randomization Analysis Based on 1400 Plasma Metabolites

Key Points

The aim is to explore the causal effects of plasma metabolites on different types of anxiety disorders using Mendelian randomization.
Utilized data from genome-wide association studies (GWAS) on plasma metabolites.
Conducted Mendelian randomization analysis to assess the relationship between metabolites and anxiety types.
Evaluated instrumental variable compliance, heterogeneity, and horizontal pleiotropy, followed by sensitivity analyses.
Identified common risk metabolites across generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder (PD).
Five specific risk markers for GAD found, including 3-hydroxy-2-ethylpropionate and the glutarate to salicylate ratio.
Unique risk marker for SAD: 5-hydroxyhexanoate.
Potential risk metabolites for PD include arabitol/xylitol and 2-hydroxy-3-methylvalerate.

Abstract

ABSTRACT Background Different anxiety types demonstrate overlapping clinical features while retaining distinct characteristics, often leading to diagnostic challenges. Existing diagnostic approaches predominantly rely on symptom‐based criteria, which may result in ambiguity. The identification of biomarkers is essential for elucidating the metabolomic mechanisms underlying anxiety, thereby informing improved diagnostic and therapeutic strategies. Methods We conducted a Mendelian randomization (MR) study, utilizing data from genome‐wide association studies (GWAS) on plasma metabolites and three anxiety types. The study meticulously evaluated instrumental variable, as well as heterogeneity, horizontal pleiotropy, and directionality, supplemented by sensitivity analyses. Results Initial MR analysis identified common risk metabolites across the three anxiety subtypes. Subsequent sensitivity analyses revealed five specific generalized anxiety disorder (GAD) risk markers, including 3‐hydroxy‐2‐ethylpropionate (OR = 1.248, P IVW = 0.012) and the glutarate (C5‐DC) to salicylate ratio (OR = 1.314, P IVW = 0.007). Among social anxiety disorder (SAD) risk markers, 5‐hydroxyhexanoate (OR = 1.005, P IVW = 0.010) was unique. Potential panic disorder (PD) risk metabolites were identified as arabitol/xylitol (OR = 1.002, P IVW = 0.011), 2‐hydroxy‐3‐methylvalerate (OR = 1.002, P IVW = 0.008), and the AMP to phosphate ratio (OR = 1.003, P IVW = 0.004). Protective factors for GAD included X‐17354 (OR = 0.739, P IVW = 0.023) and the salicylate to citrate ratio (OR = 0.754, P IVW = 0.010). Conclusion This study highlights potential metabolomic pathways involved in the shared and distinct clinical features of GAD, SAD, and PD. These findings suggest novel biomarkers for developing targeted treatments for anxiety disorders.This study investigates the causal relationship between plasma metabolites and three common types of anxiety disorders using MR analysis. Our findings propose a novel direction for utilizing metabolites as biomarkers in the diagnosis and treatment of anxiety disorders.

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