cfGWAS reveal genetic basis of cell-free DNA end motifs

Cell-free DNA (cfDNA) consists of degraded DNA fragments released into body fluids. Its genetic and pathological information makes it useful for prenatal testing and early tumor detection. However, the mechanisms behind cfDNA biology are largely unknown. In this study, for the first time, we conduct a genome-wide association study (GWAS) to explore the genetic basis of cfDNA end motif frequencies, termed cfGWAS, in 28,016 pregnant women. We identify 15 study-wide significant loci, including the well-known cfDNA-related genes DFFB and DNASE1L3, as well as novel genes potentially involved in cfDNA biology, such as PANX1 and DNASE1L1. The findings are further verified through three independent GWAS studies and experimental validation in knockout mice and cell lines. Subsequent analyses reveal strong causal relationships of leukocytes, especially neutrophils, with cfDNA features. In summary, we introduce the cfGWAS, revealing the genetic basis of cfDNA biology on a genome-wide scale. Novel knowledge uncovered by this study promises to revolutionize liquid biopsy technology and lead to potential new drugs targeting certain diseases. Given that millions of cfDNA whole genome sequencing data have been generated from clinical testing, the potential of this paradigm is enormous.