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Cited by 114Single-cell and spatial transcriptomicsGenetic Associations and EpidemiologyAdipose Tissue and Metabolism

Cell-Type Heterogeneity in Adipose Tissue Is Associated with Complex Traits and Reveals Disease-Relevant Cell-Specific eQTLs

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Glastonbury, Craig A., Couto Alves, Alexessander, El-Sayed Moustafa, Julia S., Small, Kerrin S.·2019·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2019.03.025PMC PMC6556877

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Abstract

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.

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  • Visceral adipose fat predominantly comprises adipocytes, endothelial cells, and macrophages.

    “Visceral adipose fat is known to predominantly comprise adipocytes, endothelial cells, and macrophages.53”

    From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [53]

    The Results (Estimation of Relative Cell-Type Proportions; page unavailable) identify adipocytes, endothelial cells, and macrophages as major estimated cell types, but the analyzed biopsies were subcutaneous. The Methods (GTEx RNA-Seq Dataset; page unavailable) also specifies subcutaneous samples. Visceral fat was measured as a body-fat trait, not sampled to establish its cellular composition, so the claim’s visceral-specific wording is unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Glastonbury, C. A., Couto Alves, A., El-Sayed Moustafa, J. S., & Small, K. S.
Affiliations
King's College London (GB)
Corresponding author
  • Glastonbury, Craig A.
  • Small, Kerrin S.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2019-06
Volume
104
Issue
6
Pages
1013-1024
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2019.03.025
PMC
PMC6556877
OpenAlex
W2951804967
Cited by
114
References
5
Citations by year
2026: 11 · 2025: 9 · 2024: 12 · 2023: 26 · 2022: 16 · 2021: 15 · 2020: 19 · 2019: 6
FWCI
4.80
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
Funders
  • Medical Research Council (MR/L01999X/1, MR/M004422/1, MR/L016311/1)
  • Seventh Framework Programme
  • Wellcome Trust
  • National Institute for Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
adipose tissue, cellular heterogeneity, cell type composition, expression quantitative trait loci, obesity, body fat distribution, adipocytes, CD4+ T cells, microvascular endothelial cells, co-expression network, transcriptome deconvolution
MeSH terms
Adipose Tissue, Adult, Aged, Aged, 80 and over, Female, Humans, Inflammation, Male, Middle Aged, Obesity, Phenotype, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Gene Expression Profiling, Quantitative Trait Loci, Genome-Wide Association Study, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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