Genome-wide Pleiotropy Analysis Reveals Shared Genetic Associations between Type 2 Diabetes Mellitus and Subcortical Brain Volumes

Type 2 diabetes mellitus (T2DM), a prevalent metabolic disorder marked by insulin resistance and hyperglycemia, has been linked to volumetric changes in subcortical regions, yet the genetic basis of this relationship remains unclear. We analyzed genome-wide association study summary data for T2DM and 14 subcortical volumetric traits, using MiXeR to quantify shared genetic architecture and applying conditional/conjunctional false discovery rate analyses to detect novel and shared genomic loci. Enrichment and gene expression analyses were subsequently performed to explore the biological functions and mechanisms of genes associated with these loci. We observed a substantial proportion of trait-influencing variants shared between T2DM and subcortical structures, with Dice coefficients ranging from 22.4% to 49.6%. Additionally, 70 distinct loci were identified as being jointly associated with T2DM and subcortical volumes, 5 and 22 of which were novel for T2DM and subcortical volumes, respectively. The 769 protein-coding genes mapped to these shared loci are enriched in metabolic and neurodevelopmental pathways and exhibit specific developmental trajectories, with 117 genes showing expression levels linked to both T2DM and subcortical structures. This study uncovered polygenic overlap between T2DM and subcortical structures, deepening our comprehension of the genetic factors linking metabolic disorders and brain health.