The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity
We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity (277 unique genes; false discovery rate < 10%). Since circulating EVs may have broad origin, we compared this obesity EV transcriptome with expression from human visceral-adipose-tissue-derived EVs from freshly collected and cultured biopsies from the same obese individuals, observing high concordance. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by body mass index-associated SNPs (p < 5 × 10<sup>-</sup>8) from a large-scale genome-wide association study (GWAS). Using a phenome-wide association study of the regulatory SNPs for the EV-derived transcripts, we identified a substantial enrichment for inflammatory phenotypes, including type 2 diabetes. Collectively, these findings represent the convergence of the GWAS (genetics), epigenomics (transcript regulation), and EV (liquid biopsy) fields, enabling powerful future genomic studies of complex diseases.
Authors
- Evan D. Rosen (ORCID: https://orcid.org/0000-0003-4603-708X)
- Worawan B. Limpitikul (ORCID: https://orcid.org/0000-0001-6171-9906)
- Emeli Chatterjee (ORCID: https://orcid.org/0000-0002-4515-1473)
- Kaushik V Amancherla (ORCID: https://orcid.org/0000-0003-3379-5834)
- Ravi V. Shah (ORCID: https://orcid.org/0000-0002-4471-7156)
- Charles R. Flynn (ORCID: https://orcid.org/0000-0002-3749-0598)
- Saumya Das (ORCID: https://orcid.org/0000-0002-4521-4606)
- Michael J. Betti (ORCID: https://orcid.org/0000-0001-8394-6202)
- Karen Flanders
- Marta García-Contreras (ORCID: https://orcid.org/0000-0001-8014-7966)
- Margo P. Emont (ORCID: https://orcid.org/0000-0001-9873-2784)
- Quanhu Sheng (ORCID: https://orcid.org/0000-0001-8951-9295)
- Matthew Hutter (ORCID: https://orcid.org/0000-0001-9953-8385)
- Priyanka Gokulnath (ORCID: https://orcid.org/0000-0003-2813-330X)
- Denise W. Gee
- Danxia Yu (ORCID: https://orcid.org/0000-0002-1710-9382)
- Parul Sahu (ORCID: https://orcid.org/0000-0001-8864-4043)
- Eric R. Gamazon (ORCID: https://orcid.org/0000-0003-4204-8734)
- Olivia Rosina Whittaker
- Guoping Li (ORCID: https://orcid.org/0000-0003-3874-0744)
- Jonathan D. Brown (ORCID: https://orcid.org/0000-0002-0359-6167)
- Kathy Luong
- Kendall Jensen
- Christopher Azzam
Institutions
- Broad Institute (US)
- Translational Genomics Research Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Massachusetts General Hospital (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1016/j.xgen.2025.100925
- Citations
- 3
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences