GWAS shows the genetics behind cell-free DNA and highlights the importance of p.Arg206Cys in DNASE1L3 for non-invasive testing

• Published in: Cell reports (Cambridge) 2024-10, Vol.43 (10), p.114799, Article 114799
• Main Authors: Linthorst, Jasper, Nivard, Michel, Sistermans, Erik A.
• Format: Article
• Language: English
• Subjects: cell-free DNA; DFFB; DNASE1L3; fetal fraction; fragmentomics; NIPT; PADI4; PANX1; rs35677470; VeriSeq
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114799

The properties of cell-free DNA (cfDNA) are intensely studied for their potential as non-invasive biomarkers. We explored the effect of common genetic variants on the concentration and fragmentation properties of cfDNA using a genome-wide association study (GWAS) based on low-coverage whole-genome sequencing data of 140,000 Dutch non-invasive prenatal tests (NIPTs). Our GWAS detects many genome-wide significant loci, functional enrichments for phagocytes, liver, adipose tissue, and macrophages, and genetic correlations with autoimmune and cardiovascular disease. A common (7%) missense variant in DNASE1L3 (p.Arg206Cys) strongly affects all cfDNA properties. It increases the size of fragments, lowers cfDNA concentrations, affects the distribution of cleave-site motifs, and increases the fraction of circulating fetal DNA during pregnancy. For the application of NIPT, and potentially other cfDNA-based tests, this variant has direct clinical consequences, as it increases the odds of inconclusive results and impairs the sensitivity of NIPT by causing predictors to overestimate the fetal fraction. [Display omitted] •Common variants affect properties of plasma cell-free DNA•p.Arg206Cys in DNASE1L3 strongly affects the size of cell-free DNA fragments•Fragmentomics-based fetal fraction predictors are affected by p.Arg206Cys•Genetics behind cfDNA overlaps with autoimmune and cardiovascular diseases Linthorst et al. show that a GWAS using data from 140,000 Dutch non-invasive prenatal tests (NIPTs) identifies many loci that affect the concentration and fragmentation properties of cell-free DNA in plasma. Among these, the p.Arg206Cys variant in DNASE1L3 accounts for the most variation and poses challenges for cfDNA-based diagnostics, like NIPTs.