Innovative Analytical Methods for DNA Methylation Age

项目总结/摘要 随着美国人口在未来几年继续老龄化，需要生物措施和生物标志物， 老龄化问题日益紧迫。寻找和验证衰老的生物标志物继续吸引研究 努力，但成效有限。 表观遗传修饰对衰老的生物学过程是潜在的关键（Ben-Avraham et al. 2012年）。最近，DNA甲基化水平（DNAm）已被确定为用于定义DNA甲基化的有用工具。 生物学年龄，因为Hannum等人（2013）和Horvath（2013）都在多个基因座结合DNAm来量化 人类衰老这个“DNA甲基化年龄”预测了生命后期的全因死亡率（Marioni et al. 2015）。 Hannum和Horvath都应用了超高维（~ 485 K DNA甲基化标记）变量 选择方法与弹性净罚（Zou和Hastie 2005），以获得他们的表观遗传年龄指数。 然而，在这些研究人员的原始方法中存在一些问题。在这份补助金中，我们建议 使用超高维DNA甲基化标记的更准确和更强大的表观遗传年龄模型。我们 也考虑纵向DNAm数据。我们会开发和发放一套方便使用的统计软件 该软件包将使研究人员能够轻松实现这些方法。我们将把我们的方法应用于两个 大型纵向队列研究：年轻人冠状动脉风险发展（CARDIA）和多因素 动脉粥样硬化的种族研究（梅萨）。 我们的发现可能说明了传统和创新风险因素的生物学机制， 死亡率，并发现更准确和可靠的生物老化标志物。潜在的临床、生活方式和 因此，可以开发用于健康老龄化的药物干预。

Project Summary/Abstract As the US population continues to age in the coming years, the need for biological measures and biomarkers of aging becomes increasingly urgent. Finding and validating biomarkers of aging continues to attract research efforts, but with limited success. Epigenetic modifications are potentially critical to the biological processes that underlie aging (Ben-Avraham et al. 2012). More recently, DNA methylation levels (DNAm) have been identified as useful tools for defining biological age, as Hannum et al. (2013) and Horvath (2013) both combined DNAm at multiple loci to quantify human aging. This “DNA methylation age” predicted all-cause mortality later in life (Marioni et al. 2015). Both Hannum and Horvath applied the ultra-high dimensional (~485K DNA methylation markers) variable selection methodology with elastic net penalty (Zou and Hastie 2005) to derive their epigenetic age indices. However, there are several issues in the original approaches by these researchers. In this grant, we propose more accurate and robust epigenetic age models using ultra-high dimensional DNA methylation markers. We also consider longitudinal DNAm data. We will develop and disseminate a user-friendly statistical software package that will enable researchers to implement these methods with ease. We will apply our methods to two large longitudinal cohort studies: the Coronary Artery Risk Development in Young Adults (CARDIA) and Multi- Ethnic Study of Atherosclerosis (MESA). Our discoveries may illustrate the biological mechanisms underlying traditional and innovative risk factors for mortality and discover more accurate and reliable markers for biological aging. Potential clinical, lifestyle, and pharmaceutical interventions can thus be developed for healthy aging.