From eyes to brain: A genetic and imaging exploration of thyroid eye disease neurological effects

Observational studies have reported that thyroid eye disease (TED) may cause structural and functional disorders in the brain, However, it remains uncertain whether this relationship is causal. Genetic data were obtained from the Finn Gen R11 database, yielding 587 imaging-derived phenotypes (IDPs). Single-nucleotide polymorphisms associated with TED were selected as instrumental variables, and multi-variable regression models combined with sensitivity analyses (including Cochran's Q test, MR-Egger regression, and leave-one-out analysis) were applied to evaluate the potential causal relationships between TED and these IDPs. In addition, we recruited 90 patients with TED (49 with mild disease and 41 with moderate to severe disease) along with 50 healthy controls to establish a clinical cohort. White matter microstructural alterations across different disease stages were assessed using tract-based spatial statistics (TBSS) based on diffusion tensor imaging and neurite orientation dispersion and density imaging, and these changes were further correlated with clinical indicators and rating scales. Inverse Mendelian randomization analysis revealed a significant causal relationship between TED and 26 IDPs associated with correlated fibers, brainstem nerve bundles, joint fiber regions, and projection fiber regions (false discovery rate <0.05). TBSS further revealed the evolutionary pattern of white matter structure at different levels of disease and was strongly associated with visual function, ocular symptoms, and emotional state. The combination of the two revealed abnormalities in the microstructure of white matter pathways in the anterior thalamic radiation, superior longitudinal fasciculus, and uncinate fasciculus. This study is the first to systematically assess the causal relationship between TED and cerebral white matter microstructure from both genetic and imaging levels. The two perspectives systematically reveal the potential impact of TED on the central nervous system, providing new evidence for the study of the neural mechanisms of TED and a theoretical basis for future clinical early screening and multidisciplinary intervention strategies.