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

项目摘要/摘要 出生患病率约为1/100，先天性心脏病是最常见的出生 出生缺陷和出生缺陷相关婴儿死亡的主要原因。CHDS是无法治愈的，而且没有 以人口为基础的预防战略。此外，大多数冠心病的具体原因尚不清楚。中国存在的差距 我们对先心病病因的理解阻碍了我们预防先心病的能力。因此，我们的长期目标是 研究的目的是确定冠心病的原因，并利用这一知识制定冠心病预防策略。至 为此，我们进行了一项基因水平的、全基因组范围的圆锥干心脏缺陷(CTD)的相关性研究。 母系基因。这项研究的结果提出了一种新的假设，即母体基因 通过存在于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性基因称为母性基因。 效应基因(Megs)。在我们的研究中，哺乳动物的MEGs在母体中有2-3倍的丰富 与CTD最显著相关的基因(p&lt；0.05)。我们在这项建议中的目标是确定 与CTD相关联的特定Megs以及这些Megs中的变体。具体地说，我们的工作 建议研究的假设是，MEGs子集的母体基因型与 CTD的风险和这些关联延伸到其他类型的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：1465 来自费城儿童医院的病例-父母三人组(670个CTD 1；478个CTD2；317个LSL)；以及547个三人组 (355个CTD，192个LSL)，来自儿科心脏基因组学联盟。在目标1中，我们将确定具体的 Megs，以及这些Megs中的变种，推动了观察到的Meg浓缩。在目标2中，我们将 评估MEG在LSL中的作用，以建立MEG-CTD相关性的特异性。总而言之，我们的初步数据 支持一种新的假说，即母体基因在先天性心脏病发生中的作用。 后代。这一假说的确认将为我们提供新的视角，了解CHD的原因，或许还有其他 结构性先天缺陷。因此，在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努力。

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.