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 conducted a GWAS study to explore the genetic basis of cfDNA features, termed cfGWAS, in 28,016 pregnant women. We identified 84 significant loci, including well-known cfDNA-related genes DFFB and DNASE1L3, and numerous novel genes potentially involved in cfDNA biology, including PANX1 and DNASE1L1. The findings were further verified through independent GWAS and experimental validation in knockout mice and cell lines. Subsequent analyses revealed strong causal relationships of hematological indicators on cfDNA features. In summary, we presented the first cfGWAS, revealing the genetic basis of cfDNA biology from genome-wide scale. Novel knowledge uncovered by this study keep the promise to revolutionize liquid biopsy technology and potential new drug targeted for certain disease. Given exist of the millions cfDNA whole-genome-sequencing data generated from clinical testing, the potential of this paradigm is enormous.

The authors have declared no competing interest.

This study was supported by National Natural Science Foundation of China (No.32171441), National Key Research and Development Program of China (No.2023YFC2605400, No.2022YFC2502402), Guangzhou Basic and Applied Basic Research Foundation (No.202201010189), Open Project of State Key Laboratory of Respiratory Disease (No.SKLRD-OP-202309), the Innovation Platform for Academicians of Hainan Province (No.YSPTZX202118), Key-Area Research and Development Program of Guangdong Province (No.2023B0303040001), the Shenzhen Key Laboratory of Genomics (No.CXB200903110066A), Guangdong Provincial Key Laboratory of Human Disease Genomics (No.2020B1212070028), Guangdong Provincial Key Laboratory of Genome Read and Write (No.2017B030301011), and the China National GeneBank.

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Ethics committee of Wuhan Childrens Hospital gave ethical approval for this work Ethics committee of the Bioethics and Biosafety of Beijing Genomics Institude gave ethical approval for this work

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