Department of Human Genetics, Amsterdam UMC Location VU, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands; Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, the Netherlands.
Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands; Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
Cell Rep. 2024 Oct 22;43(10):114799. doi: 10.1016/j.celrep.2024.114799. Epub 2024 Sep 25.
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.
无细胞游离 DNA（cfDNA）的特性因其作为非侵入性生物标志物的潜力而受到广泛研究。我们利用基于 140,000 例荷兰无创产前检测（NIPT）低覆盖全基因组测序数据的全基因组关联研究（GWAS），探讨了常见遗传变异对 cfDNA 浓度和片段特性的影响。我们的 GWAS 检测到许多全基因组显著位点，这些位点与吞噬细胞、肝脏、脂肪组织和巨噬细胞的功能富集有关，并且与自身免疫和心血管疾病存在遗传相关性。DNASE1L3（p.Arg206Cys）中的一种常见（7%）错义变异强烈影响所有 cfDNA 特性。它增加了片段的大小，降低了 cfDNA 浓度，影响了切割位点基序的分布，并增加了妊娠期间循环胎儿 DNA 的比例。对于 NIPT 的应用，以及其他潜在的 cfDNA 检测，这种变体具有直接的临床后果，因为它增加了不确定结果的几率，并通过导致预测因子高估胎儿分数，从而降低了 NIPT 的灵敏度。
