Cell-Type Composition Affects Adipose Gene Expression Associations With Cardiometabolic Traits.

Area of Science:

• Genomics
• Metabolic disease research
• Adipose tissue biology

Background:

• Adipose tissue is key to cardiometabolic health but is cell-type heterogeneous.
• Understanding gene expression in adipose tissue can illuminate disease mechanisms.
• Previous studies often overlook cell-type contributions to gene expression patterns.

Purpose of the Study:

• To investigate the impact of adipose cell-type heterogeneity on gene expression.
• To identify gene expression associations with cardiometabolic traits while accounting for cell-type proportions and BMI.
• To refine models for discovering genes involved in cardiometabolic diseases.

Main Methods:

• Estimated cell-type proportions in 859 subcutaneous adipose tissue samples using bulk RNA sequencing and single-nuclear RNA-seq data.
• Assessed associations between cell-type proportions and cardiometabolic traits (e.g., BMI).
• Utilized statistical models incorporating gene expression, cell-type proportions, and BMI to identify significant trait-gene associations.

Main Results:

• Cell-type proportions, such as macrophage and adipocyte levels, correlated with BMI.
• Optimal statistical models for >79% of gene expression associations included cell-type proportions as a covariate.
• Identified 2,664 significant gene expression associations for 1,252 genes across 14 cardiometabolic traits after adjustment.

Conclusions:

• Cell-type heterogeneity significantly influences gene expression patterns in adipose tissue.
• Modeling cell-type proportions is essential for accurately identifying gene expression associations with cardiometabolic traits.
• This approach enhances the discovery of genes and mechanisms underlying cardiometabolic diseases.