Maternal Genes that Control Early Embryonic Development as Risk Factors for Congenital Heart Defects

项目总结/摘要 先天性心脏病（CHD）是最常见的出生缺陷，其出生患病率约为1/100。 出生缺陷和与出生缺陷有关的婴儿死亡率的主要原因。冠心病不能治愈， 以人口为基础的预防战略。此外，大多数CHD的具体原因尚不清楚。的空白 我们对冠心病病因的理解阻碍了我们预防冠心病的能力。因此，我们的长期目标是 研究的目的是确定冠心病的原因，并利用这些知识来制定冠心病预防策略。到 为此，我们进行了圆锥动脉干心脏缺陷（CTD）的基因水平、全基因组关联研究， 母亲的基因型这项研究的结果提出了新的假设，即母亲的基因型 通过卵母细胞中的母体基因产物影响胚胎心脏发育， 胚胎发育以这种方式影响胚胎发育的母体基因称为母性基因 效应基因（MEGs）。在我们的研究中，有2-3倍的哺乳动物MEG富集在母亲的 与CTD最显著相关的基因（p<0.05）。我们提出这项建议的目的，是找出 与CTD相关的特定MEG以及这些MEG中的变体。具体来说，我们的工作 这项研究的假设是，母亲基因型的一个子集的MEG与 CTD的风险和这些相关性延伸到其他类型的CHD，特别是左侧心脏病变（LSL）。 我们将通过对来自三个大型独立研究队列的数据进行二次分析来实现我们的目标： 来自费城儿童医院的病例-父母三人组（670例CTD 1; 478例CTD 2; 317例LSL）和547例三人组 (355 CTD，192 LSL）。在目标1中，我们将确定具体的 MEG，以及这些MEG中的变体，这些变体驱动了所观察到的MEG富集。在目标2中，我们将 评估LSL中的MEG，以确定MEG-CTD关联的特异性。总之，我们的初步数据 为一种新的假说提供支持，该假说认为母体基因型在CHD的发生中起作用， 后代这一假说的证实将为冠心病的病因提供新的见解，也许， 结构性出生缺陷因此，本申请中提出的研究有可能显著影响 出生缺陷流行病学和遗传学领域，以及预防出生缺陷的公共卫生工作。

Project Summary/Abstract With a birth prevalence of approximately 1/100, congenital heart defects (CHDs) are the most common birth defects and the leading cause of birth defect related infant mortality. CHDs cannot be cured and there are no population-based prevention strategies. Further, the specific causes of most CHDs are unknown. The gaps in our understanding of the causes of CHDs hamper our ability to prevent CHDs. Hence, the long-term goal of our research is to identify the causes of CHDs and to use this knowledge to develop CHD prevention strategies. To this end, we conducted a gene-level, genome-wide association study of conotruncal heart defects (CTDs) and the maternal genotype. The results of this study suggest the novel hypothesis that the maternal genotype influences embryonic heart development via maternal gene products present in the oocyte that direct early embryonic development. Maternal genes that affect embryonic development in this way are called maternal effect genes (MEGs). In our study, there was a 2-3 fold enrichment of mammalian MEGs among the maternal genes that were most significantly associated with CTDs (p<0.05). Our objective in this proposal is to identify the specific MEGs, and the variants within these MEGs, that are associated with CTDs. Specifically, our working hypothesis for the proposed studies is that maternal genotypes for a subset of MEGs are associated with the risk of CTDs and these associations extend to other types of CHDs, specifically left-sided cardiac lesions (LSLs). We will achieve our aims through secondary analyses of data from three large, independent, study cohorts: 1465 case-parent trios (670 CTD1; 478 CTD2; 317 LSLs) from the Children’s Hospital of Philadelphia; and 547 trios (355 CTDs, 192 LSLs) from the Pediatric Cardiac Genomics Consortium. In Aim 1, we will identify the specific MEGs, and the variants within these MEGs, that are driving the observed MEG enrichment. In Aim 2, we will evaluate MEGs in LSLs, to establish the specificity of MEG-CTD associations. In summary, our preliminary data provide support for a novel hypothesis about the role of the maternal genotype in the development of CHDs in offspring. Confirmation of this hypothesis would provide new insight into the causes of CHDs and, perhaps, other structural birth defects. Hence, the studies proposed in this application have the potential to significantly affect the fields of birth defect epidemiology and genetics, as well as public health efforts to prevent birth defects.