A fundamental challenge in human genetics is determining how variation in regulatory DNA shapes complex traits and disease risk. Chromatin quantitative trait loci (cQTLs) can address this challenge by revealing the effects of disease-linked genetic variants on regulatory element activity. Discovering cQTLs in disease-relevant tissues at scale remains challenging, however. To address this limitation, we leveraged advances in epigenomic liquid biopsy. We profiled histone modifications in circulating chromatin from patients with cancer to identify cell-free chromatin QTLs (cfcQTLs). By sampling cancer-derived chromatin in plasma, we captured cfcQTLs affecting regulatory elements from diverse non-hematologic tissues, as well as developmentally restricted elements that are reactivated in cancer (enriched 16-fold). Applying a cistrome-wide association study (CWAS), we linked 4,891 cfcQTLs to 1,011 traits and diseases. Developmentally restricted cfcQTLs that were not found in white blood cells were associated with 22.7 traits per 100 QTLs, compared to 0.58 for WBC-restricted cQTLs, underscoring the power of cfcQTLs for capturing genetic variation that shapes phenotypes. We extended our approach beyond germline variants to non-coding somatic mutations in cancer by measuring the activating effects of TERT promoter mutations from circulating chromatin. This work provides a path to scalable discovery of cQTLs across tissues, diseases, and populations to dissect the genetics of common diseases, enabled by the ease of sampling blood.
