학술논문
Cell-Type Composition Affects Adipose Gene Expression Associations With Cardiometabolic Traits.
Document Type
Article
Author
Brotman, Sarah M.; Oravilahti, Anniina; Rosen, Jonathan D.; Alvarez, Marcus; Heinonen, Sini; van der Kolk, Birgitta W.; Fernandes Silva, Lilian; Perrin, Hannah J.; Vadlamudi, Swarooparani; Pylant, Cortney; Deochand, Sonia; Basta, Patricia V.; Valone, Jordan M.; Narain, Morgan N.; Stringham, Heather M.; Boehnke, Michael; Kuusisto, Johanna; Love, Michael I.; Pietiläinen, Kirsi H.; Pajukanta, Päivi
Source
Subject
*GENE expression
*LOCUS (Genetics)
*GENOME-wide association studies
*RNA sequencing
*ADIPOSE tissues
*ADIPOSE tissue diseases
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Language
ISSN
0012-1797
Abstract
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. [ABSTRACT FROM AUTHOR]