Mendelian randomization analysis of the causal associations between blood metabolites and two autoimmune thyroid diseases

Abstract:

Background and Aims Autoimmune thyroid disease (AITD) are closely associated with metabolic dysregulation, but the causal role of specific metabolites remains unclear. This study aimed to systematically evaluate the causal relationships between approximately 1 400 blood metabolites and two major AITD subtypes-Graves' disease (GD) and Hashimoto's thyroiditis (HT)-using a two-sample Mendelian randomization (MR) approach, to identify potential risk or protective metabolites and provide genetic evidence for mechanistic studies and targeted metabolic interventions.Methods Summary-level genome-wide association study (GWAS) data for blood metabolites and AITDs were analyzed using inverse-variance weighted MR as the primary method, supplemented by MR-Egger, weighted median, and mode-based methods. Heterogeneity, pleiotropy, and robustness were assessed through Cochran's Q test, horizontal pleiotropy test, and leave-one-out analyses.Results Forty-nine metabolites showed significant causal associations with GD and 89 with HT. Hexanoylglutamine and ceramide (d18∶1/16∶0) were identified as GD risk factors, while N2, N2-dimethylguanosine and β-hydroxyisovalerylcarnitine were protective. Pregnanediol sulfate and theobromine were associated with increased HT risk, whereas dihomo-linolenate (20:3n3 or n6) and caprylate appeared protective. The α-ketoglutarate/succinate ratio was positively associated with both diseases, suggesting a shared metabolic risk pathway.Conclusion This MR study provides genetic evidence supporting causal links between multiple blood metabolites and GD or HT. Several metabolites may serve as predictive or protective biomarkers, offering novel insights into the pathophysiology, early screening, and personalized metabolic intervention strategies for AITDs.