Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
Department of Pediatrics, Center for Genomic and Computational Biology, Duke University, Durham, NC 27705, USA.
Sci Adv. 2020 Dec 2;6(49). doi: 10.1126/sciadv.abc8696. Print 2020 Dec.
While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWASs), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of functional genomic annotations in human cell types relevant to pregnancy and PTB. We generated transcriptome (RNA-seq), epigenome (ChIP-seq of H3K27ac, H3K4me1, and H3K4me3 histone modifications), open chromatin (ATAC-seq), and chromatin interaction (promoter capture Hi-C) annotations of cultured primary decidua-derived mesenchymal stromal/stem cells and in vitro differentiated decidual stromal cells and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. Using these resources, we uncovered additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.
虽然早产（PTB）的遗传成分早已被认识，并在最近的全基因组关联研究（GWAS）中进行了定位，但 PTB 的分子决定因素仍然难以捉摸。这部分归因于与妊娠和 PTB 相关的人类细胞类型中功能基因组注释的不完全可用性。我们生成了培养的主要蜕膜衍生间充质基质/干细胞和体外分化的蜕膜基质细胞的转录组（RNA-seq）、表观基因组（H3K27ac、H3K4me1 和 H3K4me3 组蛋白修饰的 ChIP-seq）、开放染色质（ATAC-seq）和染色质相互作用（启动子捕获 Hi-C）注释，并开发了一种计算框架，将这些功能注释与 56384 名女性妊娠持续时间 GWAS 的结果进行整合。使用这些资源，我们发现了与妊娠持续时间相关的其他位点和相关位点的靶基因。我们的策略说明了与妊娠相关细胞类型的功能注释如何有助于 PTB 及其他可能与妊娠相关的疾病的 GWAS 的实验随访。
