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

Understanding differences in adipose gene expression between individuals with different levels of clinical traits may reveal the genes and mechanisms leading to cardiometabolic diseases. However, adipose is a heterogeneous tissue. To account for cell-type heterogeneity, we estimated cell-type proportions in 859 subcutaneous adipose tissue samples with bulk RNA sequencing (RNA-seq) using a reference single-nuclear RNA-seq data set. Cell-type proportions were associated with cardiometabolic traits; for example, higher macrophage and adipocyte proportions were associated with higher and lower BMI, respectively. We evaluated cell-type proportions and BMI as covariates in tests of association between >25,000 gene expression levels and 22 cardiometabolic traits. For >95% of genes, the optimal, or best-fit, models included BMI as a covariate, and for 79% of associations, the optimal models also included cell type. After adjusting for the optimal covariates, we identified 2,664 significant associations (P ≤ 2e−6) for 1,252 genes and 14 traits. Among genes proposed to affect cardiometabolic traits based on colocalized genome-wide association study and adipose expression quantitative trait locus signals, 25 showed a corresponding association between trait and gene expression levels. Overall, these results suggest the importance of modeling cell-type proportion when identifying gene expression associations with cardiometabolic traits. ARTICLE HIGHLIGHTS: Our goal was to create a resource of trait-gene expression associations on a genome-wide scale across several cardiometabolic traits that accounts for cell-type heterogeneity. We aimed to determine whether cell-type composition affects trait-gene associations. We found that adjusting for both BMI and cell-type proportion is the best-fitting model for most trait-gene expression associations in adipose tissue. We identified 2,664 significant associations for 1,252 genes and 14 traits using a linear model that accounts for cell-type composition and BMI. Our findings suggest that cell-type composition should be considered when assessing the association between adipose gene expression and cardiometabolic traits.