High-resolution Genetic Mapping of Maternal Effects and Epistatic Suppressors of Congenital Heart Disease Risk

项目总结/摘要 先天性心脏病（CHD）是最常见的先天性异常，其导致显著的 新生儿的发病率和死亡率。尽管外科手术的巨大进步降低了新生儿CHD的死亡率， 和儿童，这些病人是无法治愈的。这些儿童中的许多人长大后患上了严重的疾病， 缩短了成年人的寿命显然，我们需要战略， 干预和预防。这一奋进的第一步是了解CHD的原因。 令人惊讶的是，环境和突变估计只能解释不到三分之一的CHD病例。在许多 然而，在某些情况下，即使重要的心脏基因发生突变，也不会发生心脏缺陷。这凸显 遗传修饰剂在CHD发病机制中的关键作用。试图识别这些修饰基因的努力已经取得了进展。 在人类身上取得了微小的成功。这促使我们转向动物模型，在那里我们可以控制效果 环境和遗传学。 我们的小鼠模型通过Nkx 2 -5的杂合突变在易感人群中复制CHD风险， 一种重要的心脏转录因子然后，我们使用近交系杂交和数量遗传学方法， 在Nkx 2 -5+/-小鼠中鉴定改变CHD风险的遗传多态性。通过这个模型系统，我们 无意中证实了在人类中的观察，即高龄母亲的后代患冠心病的风险增加 即使排除了非整倍体我们还确定，这种风险是由于高龄母亲的因素，而不是年龄 鸡蛋值得注意的是，老年母亲的自愿运动足以将CHD风险降低到基线水平。 随后的研究表明，母亲衰老风险的大小因遗传因素而异。 我们老鼠的背景这表明，年龄风险是一个数量性状，调节母亲的因素， 它可以增加或抑制冠心病的风险。在单独的实验中， 在易感个体中，我发现了在多个小鼠中作为CHD风险上位抑制因子的遗传位点， 人口。如果我们能够识别出负责的基因，并模仿母亲锻炼的效果， 保护性基因位点，我们可以将这些好处转化为普通人群。我们过去的实验 用来检测单个基因所以与其去推测是哪些基因决定了母亲的年龄- 相关的风险和上位抑制冠心病，我们选择了一个谨慎和公正的方法，以确定 这些基因。我们与James Cheverud的实验室合作， 交叉作图群体以鉴定CHD修饰基因座至接近单基因分辨率。本研究将 第一个以高分辨率绘制改变CHD风险的新基因和变体，这些结果将作为 为将来研究先天性心脏病的预防提供了一个跳板。 我们提出这些具体目标： 目的1：确定高分辨率的基因位点，修改母亲的年龄相关的冠心病的风险。 目的2：定位高分辨率遗传位点，检测后代CHD风险的上位性抑制因子。

PROJECT SUMMARY / ABSTRACT Congenital heart disease (CHD) is the most common congenital anomaly, which leads to significant morbidity and mortality in newborns. Although great surgical advances have reduced CHD mortality in newborns and children, these patients are not cured. Many of these children grow up and experience serious morbidity and truncated lifespans as adults. It has become evident that we need strategies to move our efforts away from intervention and toward prevention. The first step in this endeavor is to understand the causes of CHD. Surprisingly, environment and mutations are estimated to explain less than one-third of CHD cases. In many cases, however, even when a vital cardiac gene is mutated, a heart defect does not occur. This highlights the critical role that genetic modifiers have in CHD pathogenesis. Attempts to identify these modifier genes have had marginal success in humans. This motivated us to look toward animal models, in which we can control the effects of environment and genetics. Our mouse model replicates CHD risk in susceptible people through a heterozygous mutation in Nkx2-5, an essential cardiac transcription factor. We then use inbred strain crosses and quantitative genetic methods to identify genetic polymorphisms that modify CHD risk in Nkx2-5+/- mice. Through this model system, we inadvertently confirmed observations in humans that the offspring of older mothers have an elevated risk for CHD even after ruling out aneuploidy. We also determined that this risk is due to factors within old mothers, not old eggs. Remarkably, voluntary exercise for the aging mother is sufficient to reduce CHD risk to baseline levels. Subsequent studies demonstrated that the magnitude of the maternal aging risk varied according to the genetic background of our mice. This indicates that the age risk is a quantitative trait that regulates maternal factors, which can either inflate or suppress the risk of CHD. In separate experiments focused on risk modifiers within susceptible individuals, I discovered genetic loci that act as epistatic suppressors of CHD risk in multiple mouse populations. If we were able to identify the genes responsible and mimic the effects of maternal exercise or protective genetic loci, we could translate these benefits to the general population. Our past experiments were not designed to detect individual genes. So instead of speculating about the genes responsible for the maternal age- associated risk and epistatic suppression of CHD, we have chosen a prudent and unbiased approach to identify these genes. We have partnered with the laboratory of James Cheverud to use a high-resolution, advanced intercross mapping population to identify CHD modifier loci to nearly single-gene resolution. This study will be the first to map novel genes and variants that modify CHD risk at high-resolution, and these results will serve as a springboard for future research into congenital heart disease prevention. We propose these specific aims: AIM 1: Identify high-resolution genetic loci that modify the maternal age-associated risk of CHD. AIM 2: Map high-resolution genetic loci and detect epistatic suppressors of CHD risk in the offspring.