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

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.