Genome-Wide Association Summary Statistics-Based Genetic Mapping of Brain Functional and Structural Networks in Type 2 Diabetes Mellitus and Its Complications.
TL;DR
It is revealed that the genetically predisposed higher risk of diabetic maculopathy was associated with increased salience network connectivity, shedding light on the neural drivers of diabetic pathologies.
Abstract
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.