1. Research Background
Type 2 diabetes mellitus (T2DM) is a highly prevalent metabolic disorder worldwide. Beyond glucose dysregulation, it exerts significant effects on the central nervous system. Epidemiological and neuroimaging evidence indicates that individuals with T2DM are at substantially increased risk of cognitive decline and dementia, which is closely linked to degenerative changes in brain structure—particularly within subcortical regions such as the hippocampus, amygdala, caudate, and thalamus. These regions play critical roles in memory, emotional regulation, and motor control, and have been shown to exhibit marked volume reduction and structural abnormalities in individuals with T2DM.
Current neuroimaging studies have systematically characterized the structural brain abnormalities associated with T2DM. However, the underlying genetic mechanisms driving these changes remain unclear. T2DM is a prototypical polygenic disorder, with large-scale genome-wide association studies (GWAS) having identified hundreds of associated genetic loci. Likewise, the volume and morphology of subcortical brain structures are known to be strongly influenced by genetic factors. Emerging evidence suggests potential genetic overlap between T2DM and brain structure. For instance, the T2DM risk gene TCF7L2 has been linked to amygdala volume, and the Hp 1-1 gene has been associated with hippocampal volume. Moreover, polygenic risk scores for glycated hemoglobin (HbA1c) have shown associations with gray matter volume, and the genetic risk of several hippocampal morphological traits has been related to T2DM. While these findings provide preliminary insights, a comprehensive investigation into the shared genetic architecture between T2DM and brain structural abnormalities is still lacking. Further research is needed to elucidate the underlying molecular pathways and biological mechanisms.
2. Research Progress
The authors systematically evaluated the polygenic overlap and shared genetic architecture between T2DM and the volumes of subcortical brain structures, including the bilateral thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens. MiXeR analysis revealed that T2DM has high polygenicity and low discoverability, and shares varying degrees of genome-wide genetic overlap with subcortical brain regions, with Dice coefficients ranging from 22.4% to 49.6% (Figure 1).
Using the conditional false discovery rate approach, the study identified 229 loci associated with T2DM (including 5 novel loci) and 220 loci associated with subcortical brain structures (including 16 novel loci). Furthermore, conjunctional false discovery rate analysis revealed 129 shared loci jointly associated with T2DM and subcortical volumes (Figure 2). Among them, rs429358 on chromosome 19 (located in the APOE gene) showed the strongest association with both bilateral accumbens volume and T2DM, and exhibited a high functional pathogenicity score (Figure 3A).
In the functional annotation, most of the shared SNPs were located in intronic or intergenic regions. A total of 769 protein-coding genes were mapped from the candidate SNPs, showing high expression in pancreatic, hepatic, and cardiac tissues, and were involved in various biological processes including energy metabolism, neurogenesis, and nervous system development. Developmental trajectory analysis revealed that genes shared between T2DM and multiple subcortical brain regions were highly expressed during the fetal period and gradually declined after birth, suggesting their potential role in early brain development (Figure 3).
Further transcriptome-wide association analysis (TWAS) validated the dual association of several key genes (e.g., TUFM, JAZF1) with both T2DM and the volumes of specific brain regions (Figure 4).
3. Future Perspectives
This study systematically revealed the genetic overlap between T2DM and subcortical brain structures, clarifying their shared genetic loci, shared genes and the potential biological pathways involved. This interdisciplinary work not only deepens our understanding of how T2DM affects brain health, but also promotes a shift in metabolic disease research from a traditional focus on peripheral metabolism to the central nervous system. The findings provide critical genetic evidence for risk prediction, biomarker identification, and early intervention strategies targeting T2DM-related brain structural alterations, offering new directions for clinical translation and precision prevention in the brain-metabolism interface.
Sources: https://doi.org/10.34133/research.0688
