Cell-Free DNA GWAS Reveals Importance of p.Arg206Cys in DNASE1L3 for Non-Invasive Testing

Abstract

SUMMARYProperties of cell-free DNA (cfDNA) are intensely studied for their potential as non-invasive biomarkers. We explored the effect of common genetic variants on concentration and fragmentation properties of cfDNA using a GWAS based on low-coverage whole genome sequencing data of 140.000 Dutch Non-Invasive Prenatal Tests (NIPT). Our GWAS detects many genome-wide significant loci, functional enrichments for Phagocytes, Liver, Adipose tissue, Macrophages and genetic correlations with autoimmune and cardiovascular disease. A common (7%) missense variant inDNASE1L3(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.HIGHLIGHTSCommon variants affect properties of plasma cell-free DNAp.Arg206Cys inDNASE1L3strongly affects the size of cell-free DNA fragmentsFragmentomics-based fetal fraction predictors are affected by p.Arg206CysGenetics behind cfDNA overlaps with autoimmune and cardiovascular diseases