Cell-type heterogeneity in adipose tissue is associated with complex traits and reveals disease-relevant cell-specific eQTLs
| Autor: | Craig A. Glastonbury, Alexessander Couto Alves, Kerrin S. Small, Julia S. El-Sayed Moustafa |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Multifactorial Inheritance obesity Cell type In silico Quantitative Trait Loci Adipose tissue Genomics Genome-wide association study Disease Computational biology Biology eQTL Polymorphism Single Nucleotide Article Transcriptome transcriptomics 03 medical and health sciences 0302 clinical medicine cell type composition genomics Humans Genetic Predisposition to Disease genetics Gene Genetics (clinical) Aged 030304 developmental biology Aged 80 and over Inflammation adipose 0303 health sciences Gene Expression Profiling Middle Aged interactions TwinsUK 030104 developmental biology Phenotype Adipose Tissue 030220 oncology & carcinogenesis Expression quantitative trait loci Female GTEx 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | American Journal of Human Genetics Glastonbury, C A, Couto Alves, A, El-Sayed Moustafa, J S & Small, K S 2019, ' Cell-type heterogeneity in adipose tissue is associated with complex traits and reveals disease-relevant cell-specific eQTLs ', American Journal of Human Genetics, vol. 104, no. 6, pp. 1013-1024 . https://doi.org/10.1016/j.ajhg.2019.03.025 |
| Popis: | Adipose tissue is an important endocrine organ with a role in many cardiometabolic diseases. It is comprised of a heterogeneous collection of cell types that can differentially impact disease phenotypes. Cellular heterogeneity can also confound -omic analyses but is rarely taken into account in analysis of solid-tissue transcriptomes. Here, we investigate cell-type heterogeneity in two population-level subcutaneous adipose-tissue RNA-seq datasets (TwinsUK, n = 766 and the Genotype-Tissue Expression project [GTEx], n = 326) by estimating the relative proportions of four distinct cell types (adipocytes, macrophages, CD4+ T cells, and micro-vascular endothelial cells). We find significant cellular heterogeneity within and between the TwinsUK and GTEx adipose datasets. We find that adipose cell-type composition is heritable and confirm the positive association between adipose-resident macrophage proportion and obesity (high BMI), but we find a stronger BMI-independent association with dual-energy X-ray absorptiometry (DXA) derived body-fat distribution traits. We benchmark the impact of adipose-tissue cell composition on a range of standard analyses, including phenotype-gene expression association, co-expression networks, and cis-eQTL discovery. Our results indicate that it is critical to account for cell-type composition when combining adipose transcriptome datasets in co-expression analysis and in differential expression analysis with obesity-related traits. We applied gene expression by cell-type proportion interaction models (G × Cell) to identify 26 cell-type-specific expression quantitative trait loci (eQTLs) in 20 genes, including four autoimmune disease genome-wide association study (GWAS) loci. These results identify cell-specific eQTLs and demonstrate the potential of in silico deconvolution of bulk tissue to identify cell-type-restricted regulatory variants. |
| Databáze: | OpenAIRE |
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