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

Area of Science:

• Genetics
• Neuroscience
• Metabolic Disorders

Background:

• Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with insulin resistance and hyperglycemia.
• Previous research suggests links between T2DM and volumetric changes in subcortical brain regions.
• The genetic underpinnings of the relationship between T2DM and subcortical volumes are not well understood.

Purpose of the Study:

• To investigate the shared genetic architecture between T2DM and 14 subcortical volumetric traits.
• To identify novel and shared genomic loci associated with both T2DM and subcortical volumes.
• To explore the biological functions and gene expression patterns of identified shared loci.

Main Methods:

• Genome-wide association study (GWAS) summary data for T2DM and subcortical volumes were analyzed.
• MiXeR software was used to quantify shared genetic architecture.
• Conditional/conjunctional false discovery rate analyses identified significant genomic loci.
• Enrichment and gene expression analyses were performed on identified genes.

Main Results:

• A significant proportion of variants influencing T2DM and subcortical volumes were shared, with Dice coefficients between 22.4% and 49.6%.
• Seventy distinct loci were jointly associated with T2DM and subcortical volumes, including 5 novel loci for T2DM and 22 for subcortical volumes.
• Genes mapped to shared loci are enriched in metabolic and neurodevelopmental pathways, with 117 genes showing expression linked to both T2DM and subcortical structures.

Conclusions:

• This study reveals a significant polygenic overlap between Type 2 diabetes and subcortical brain structures.
• The findings enhance understanding of the genetic factors connecting metabolic health and brain structure.
• The identified shared loci and genes provide potential targets for future research into T2DM and neurological comorbidities.