We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity. Since circulating EVs may have broad origin, we compared this obesity EV transcriptome to expression from human visceral adipose tissue derived EVs from freshly collected and cultured biopsies from the same obese individuals. 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 BMI-associated SNPs from a large-scale 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.

RS has served for a consultant for Amgen, Cytokinetics, and Thryv Therapeutics (with equity in Thryv). RS is a co-inventor on a patent for ex-RNAs signatures of cardiac remodeling and a pending patent on proteomic signatures of disease.

This work was funded by grants from American Heart Association Strategically Focused Research Network (AHA; SFRN16SFRN31280008); National Heart, Lung, and Blood Institute (1R35HL150807-01); and National Center for Advancing Translational Sciences (UH3 TR002878) to SD. RS is supported by the NIH and the AHA. GL is supported by AHA (23CDA1045944). ERG is supported by the National Human Genome Research Institute (R35HG010718 and R01HG011138), National Institute of General Medical Sciences (R01GM140287), and the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK140952). EDR is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (RC2 DK116691).

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The study was IRB-approved at Mass General Brigham, with written informed consent collected from participants before study initiation

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All data produced in the present study are available upon reasonable request to the authors