Circulating chromatin reveals effects of disease-associated variants on gene regulation

A fundamental challenge in human genetics is determining how regulatory genetic variation shapes complex traits and disease risk. Chromatin quantitative trait loci can link disease-associated variants to regulatory element activity, but mapping them in disease-relevant tissues at scale remains challenging. We leverage epigenomic liquid biopsy by profiling histone modifications in circulating chromatin from 328 cancer patients and 38 healthy individuals to identify cell-free chromatin quantitative trait loci. These loci affect regulatory element activities from diverse non-hematologic tissues and developmentally restricted elements reactivated in cancer. Through cistrome-wide association studies, we link 4891 loci to 1011 traits and diseases. Developmentally restricted loci absent in white blood cells are associated with 22.7 traits per 100 quantitative trait loci, compared to 0.58 for white-blood-cell-restricted chromatin quantitative trait loci. Here, we show that cell-free chromatin enables efficient and scalable discovery of regulatory genetic effects across tissues, diseases, and populations. Regulatory genetic variants can influence disease risk through effects on chromatin activity, but studying these effects across tissues remains challenging. Here, the authors use cell‑free chromatin profiling to identify chromatin quantitative trait loci across diverse tissues, linking regulatory variation to hundreds of human traits and diseases.