Genome-Wide Association Summary Statistics-Based Genetic Mapping of Brain Functional and Structural Networks in Type 2 Diabetes Mellitus and Its Complications.

The disruptions in brain networks have been consistently observed in type 2 diabetes mellitus (T2DM) and complications. However, the causal effects and direction between these factors have yet to be elucidated. We conducted a two-sample bidirectional MR investigation supported by multiple sensitivity analyses. The study incorporated large-scale brain functional/structural network phenotypes from UK Biobank participants, while data for T2DM and related complications were provided by the FinnGen biobank. This dual-source approach ensured a rigorous evaluation of the causal interplay between neural traits and metabolic health. The forward MR analyses revealed two resting-state functional phenotypes and three white matter structural phenotypes that are genetically linked to a higher risk of T2DM, all robust to global FDR correction (q < 0.05). Notably, the connectivity in default mode/Central executive and salience networks were associated with increased risk of T2DM (OR = 1.355, 95% CI = 1.217-1.510, P = 3.40×10-8, global FDR q < 0.05). Reverse MR analysis revealed that the genetically predisposed higher risk of diabetic maculopathy was associated with increased salience network connectivity (global FDR q < 0.05). Our results reveal significant causal associations between connectome phenotypes and T2DM, shedding light on the neural drivers of diabetic pathologies. While these findings broaden our understanding of the brain-T2DM interaction mechanism, subsequent longitudinal research is required to substantiate their relevance in a clinical setting.