A Causal Inference Study of Circulating Metabolites Mediating the Effect of Obesity‐Related Indicators on the Incidence of Anxiety Disorders

TL;DR

This study finds that higher body fat increases anxiety risk, with specific metabolites like phenylalanine and cholesterol ratios playing a key role in this link.

Contribution

The study identifies three metabolites that mediate the causal relationship between obesity and anxiety using Mendelian randomization.

Findings

Higher body fat percentage increases anxiety risk (OR = 1.1428) with mediation by phenylalanine and cholesterol ratios.

Linoleic acid ratio partially mediates the effect of body fat on anxiety, accounting for 25% of the total impact.

Phenylalanine also mediates the protective effect of certain obesity phenotypes on anxiety (7.59% of the total effect).

Abstract

Previous studies have reported an association between obesity and anxiety; however, these findings are inconclusive and subject to the risk of reverse causality.

Employing data from the UK Biobank and FinnGen Consortium, this study conducted genome‐wide association studies (GWAS) and employed a two‐sample Mendelian Randomization (MR) approach to investigate the association between genetic predictors of obesity and anxiety disorders (AD). A multivariable MR (MVMR) methodology quantified the proportion of the impact of obesity‐related indicators on AD mediated by circulating metabolites, accompanied by sensitivity analyses to assess the robustness of the results.

A univariate MR analysis demonstrated that a higher body fat percentage correlates with an elevated risk of anxiety (OR = 1.1428; p = 0.033). In contrast, increased levels of obesity and hyperalimentation were linked to a decreased risk of anxiety (OR = 0.9018; p = 0.044). Additionally, twelve circulating metabolites were identified as causally related to AD. Reverse causation MR analysis affirmed the lack of reverse causal influence of AD on obesity markers and circulating metabolites (p > 0.05). MVMR analysis revealed that body fat percentage and anxiety are interconnected through mediated pathways involving phenylalanine and the ratio of free cholesterol to total lipids in very small VLDL, with mediation effects recorded at 0.028 and 0.014, respectively. Furthermore, body fat percentage impacts anxiety via the ratio of linoleic acid to total fatty acids, demonstrating a partial mediation effect of −0.042, which accounts for 25% of the overall impact. Obesity and other hyperalimentations influence anxiety through phenylalanine, with a partial mediation effect of 0.006, accounting for 7.59% of the total effect.

This study establishes a significant causal relationship between obesity and anxiety, with three circulating metabolites playing a clear mediating role. Thus, targeting these metabolites could significantly reduce the burden of AD associated with obesity.

This Mendelian randomization study reveals that higher body fat percentage increases anxiety disorder risk (OR = 1.14), while certain obesity phenotypes show protective effects (OR = 0.90). Three key circulating metabolites—phenylalanine, the free cholesterol to total lipids ratio in very small VLDL, and the linoleic acid ratio—mediate these relationships. Phenylalanine and free cholesterol completely mediate body fat's effect on anxiety, while the linoleic acid ratio partially mediates this relationship (25% of the total effect).

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