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Cell-type composition affects adipose gene expression associations with cardiometabolic traits

Version 2 2023-09-19, 13:27
Version 1 2023-08-30, 19:30
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posted on 2023-08-30, 19:30 authored by Sarah M. Brotman, Anniina Oravilahti, Jonathan D. Rosen, Marcus Alvarez, Sini Heinonen, Birgitta van der Kolk, Lilian Fernandes Silva, Hannah J. Perrin, Swarooparani Vadlamudi, Cortney Pylant, Sonia Deochand, Patricia V. Basta, Jordan M. Valon, Morgan N. Narain, Heather M. Stringham, Michael Boehnke, Johanna Kuusisto, Michael I. Love, Kirsi H. Pietiläinen, Päivi Pajukanta, Markku Laakso, Karen L. Mohlke

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 (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 if 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.

Funding

Academy of Finland 266286 272376 314383 321428 335443 338417

Finnish Diabetes Research Foundation x

Finnish Foundation for Cardiovascular Research, Centre of Excellence of Cardiovascular and Metabolic Diseases x 0245896-3

Finnish Medical Foundation x

Government Research Funds for Helsinki University Hospital and the University of Helsinki x

Gyllenberg Foundation x

Helsinki University Hospital Research Funds x

Ida Montin Foundation x

U.S. Department of Health and Human Services > National Institutes of Health F31HL154730 R01DK062370 R01DK072193 R01DK079357 R01DK132775 R01HG010505 T32GM007092 T32HL129982 UM1DK126185

Novo Nordisk NNF10OC1013354 NNF17OC0027232 NNF20OC0060547

Orion Foundation

Paavo Nurmi Foundation

Paulo Foundation

Sigrid Juselius Foundation

History