<b>Cell-type composition affects adipose gene expression associations with cardiometabolic traits</b>

Abstract

<p>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 dataset. Cell-type proportions were associated with cardiometabolic traits; for example, higher macrophage and adipocyte proportions were associated with higher and lower body mass index (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 (<i>P</i> ≤ 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.</p><p><b>Article Highlights</b></p><p>· 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.</p><p>· We aimed to determine if cell-type composition affects trait-gene associations.</p><p>· 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.</p><p>· Our findings suggest that cell-type composition should be considered when assessing the association between adipose gene expression and cardiometabolic traits.</p>