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cfGWAS reveal genetic basis of cell-free DNA features

Zhu, H.; Zhang, Y.; Zeng, S.; Li, L.; Ou, R.; Zhang, X.; Lin, Y.; Xu, C.; Wang, L.; Zeng, G.; Zeng, J.; Li, L.; Jia, Y.; Wang, Y.; Luo, F.; Yang, M.; Hu, Y.; Li, X.; Xiao, H.; Xu, X.; Wang, J.; Zhou, A.; Zhang, H.; Jin, X.

2024-08-30 genetic and genomic medicine
10.1101/2024.08.28.24312755 medRxiv
Show abstract

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.

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