Genetically Determined Metabolites in Graves Disease: Insight From a Mendelian Randomization Study

Graves disease (GD) is a prevalent autoimmune disorder with a complex etiology. The association between serum metabolites and GD remains partially understood.

This study aimed to elucidate the causal connections between serum metabolites and predisposition to GD, examining potential genetic interplay.

A 1-sample Mendelian randomization (MR) study was conducted on the GD analysis that included 2836 cases and 374 441 controls. We utilized genome-wide association study summary data from the FinnGen project, analyzing the causal impact of 486 serum metabolites on GD. Approaches used were the inverse variance weighted methodology, Cochran's Q test, MR-Egger regression, MR-PRESSO, Steiger test, and linkage disequilibrium score regression analyses to assess genetic influence on metabolites and GD.

19 metabolites were identified as having a pronounced association with GD risk, of which 10 maintained noteworthy correlations after stringent sensitivity assessments. Three metabolites exhibited significant heritability: kynurenine (OR 3.851, P = 6.09 × 10^-4), a risk factor; glycerol 2-phosphate (OR 0.549, P = 3.58 × 10^-2) and 4-androsten-3beta,17beta-diol disulfate 2 (OR 0.461, P = 1.34 × 10^-2) were recognized as protective factors against GD. Crucially, all 3 exhibited no shared genetic interrelation with GD, further substantiating their potential causal significance in the disease.

This study unveils pivotal insights into the intricate relationships between serum metabolites and GD risk. By identifying specific risk and protective factors, it opens avenues for more precise disease understanding and management. The findings underline the importance of integrating genomics with metabolomics to fathom the multifaceted nature of GD.