Tracing the tissue origin of cell-free DNA through open chromatin footprint

Plasma cell-free DNA (cfDNA) is a promising biomarker for liquid biopsy, essential for diagnosing and monitoring diseases. Current methods for estimating tissue contributions primarily rely on methylation markers, which can damage cfDNA, limiting clinical use. While research shows cfDNA coverage near transcription start sites (TSS) of actively transcribed genes decreases due to open chromatin, a comprehensive cross-tissue atlas has been lacking. Here, we identify 2549 tissue-specific, highly expressed genes across 12 human tissues and develop the Tissue Contribution Index (TCI) to quantify tissue contributions to plasma cfDNA using TSS coverage. TCI is validated in cfDNA origin models, including pregnant women and transplant recipients, demonstrating high accuracy. We establish reference intervals using plasma cfDNA from 460 healthy individuals and explore TCI's diagnostic utility in monitoring tissue damage and predicting outcomes. This study presents a simple, cost-effective method for tissue deconvolution of cfDNA, advancing liquid biopsy for disease detection and personalized medicine.