Uncovering the genetic link between type 2 diabetes and brain structure

1. Research background

Type 2 Diabetes Mellitus (T2DM) is a very common metabolic disorder worldwide. In addition to glucoseSdys regulation, it has significant effects on the central nervous system. Epidemiological and neuroimaging evidence indicates that persons with T2DM have a considerably increased risk of cognitive decline and dementia, which is closely linked to degenerative changes in brain structure, especially in subcortical regions such as the Hippocampus, Amygdala, Caudaat and Thalamus. These regions play a crucial role in memory, emotional regulation and motor control, and it has been shown that they show clear volume reduction and structural abnormalities in people with T2DM.

Current neuroimaging investigations have systematically characterized the structural brain abnormalities that are associated with T2DM. However, the underlying genetic mechanisms that control these changes remain unclear. T2DM is a prototypic polygenic condition, in which large -scale genome -wide association studies (GWAs) have identified hundreds of associated genetic loci. Similarly, it is known that the volume and morphology of subcortical brain structures are strongly influenced by genetic factors. Upcoming evidence suggests potential genetic overlap between T2DM and brain structure. For example the T2DM riskogues TCF7L2 is linked to the amygdala volume and the HP 1-1 Gen is associated with Hippocampaal volume. In addition, polygene risk scores for glycated hemoglobin (HBA1C) have demonstrated associations with gray dust volume and the genetic risk of various hippocampal morphological properties related to T2DM is. Although these findings offer preliminary insights, there is still an extensive investigation into the shared genetic architecture between T2DM and brain -structural abnormalities. Further research is needed to clarify the underlying molecular routes and biological mechanisms.

2. Research output

The authors systematically evaluated the polygene 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 a high polygenicity and low discovery, and the shares to varying degrees of genetic -wide genetic overlap with subcortical brain areas, with dice and coefficients ranging from 22.4% to 49.6%.

With the help of the conditional false discovery speed approach, the study identified 229 Loci associated with T2DM (including 5 new Loci) and 220 Loci associated with subcortical brain structures (including 16 new loci). Furthermore, conjunctional analysis of the false discovery speed 129 Shared Loci jointly revealed with T2DM and subcortical volumes. Among them, RS429358 on chromosome 19 (located in the Apoe gene) showed the strongest association with both bilateral accumbens volume and T2DM, and showed a high functional pathogenicity score.

In the functional annotation, most shared SNPs were in intronic or intergent regions. A total of 769 protein-coding genes were mapped from the SNPs of the candidate, which showed high expression in pancreatic, liver and heart tissues and were involved in various biological processes, including energy metabolism, neurogenesis and development of the nervous system. Development process analysis showed that genes that were shared between T2DM and several subcortical brain areas were strongly expressed during the fetal period and gradually fell after birth, which suggests that their potential role in early brain development.

Further transcriptom -wide association analysis (Twas) validated the double association of various important genes (eg. TUFM” Jazf1) With both T2DM and the volumes of specific brain areas.

3. Future prospects

This study systematically revealed the genetic overlap between T2DM and subcortical brain structures, which clarifies their shared genetic loci, shared genes and potential biological routes. This interdisciplinary work not only deepens our understanding of how T2DM influences the health of the brain, but also promotes a shift in metabolic diseases of a traditional focus on peripheral metabolism to the central nervous system. The findings offer critical genetic evidence of risk prediction, biomarker identification and early intervention strategies aimed at T2DM-related structural changes in the brain, offering new directions for clinical translation and precision prevention in the interface of brain metabolism.