Trans-omics integration of multi-omics studies for male osteoporosis

总体摘要 骨质疏松症的主要特征是低骨矿物质密度（BMD），其风险在以后的生活中可能是最 在20-40岁时达到峰值BMD。虽然女性患骨质疏松症的风险较高，但男性 在骨质疏松性骨折后的发病率和死亡率要高得多。表观遗传因素 大多数BMD遗传率（>85%）（尤其是性别特异性遗传率）的基础在很大程度上是未知的 这主要是由于所使用的技术和方法的限制。针对男性骨质疏松症的研究很少。 我们的一般假设是：虽然个体组学研究（基因组/转录组/表观基因组）是有用的， 对多组学数据的综合跨组学分析将更有成效，更强大，不仅在 识别新的风险（表观）基因/变体，但最重要的是阐明它们在人类体内的功能。 本U19计划项目（PPG）的总体目标是最全面地识别/表征（epi- 基因/环境因素及其作用机制对男性骨质疏松风险的影响。我们将开创一个 通过同时在基因组-（DNA， Proj 1）、转录组（mRNA和miRNA，Proj 2）和表观基因组（DNA甲基化，Proj 3）水平， 同时考虑环境因素（项目1-3）。我们将评估性别/种族/人群特异性， 鉴定的（表型）基因（项目1-3）。此外，我们将进行深入的功能研究（如项目3所示） 详细的分子机制和功能确认特定的新的骨质疏松症易感性 基因/变种被发现。特别是，除了对个体组学数据的最新分析之外， 项目1-3分别，我们将超越地平线开发/应用创新的分析方法（核心C）， 表征不同组学内部和之间的相互作用（例如miRNA甲基化的相互作用，以及 通过DNA变体和通过miRNA/甲基化调节mRNA）。我们将（在核心C中）创新地整合这些 各种组学之间的相互作用，以鉴定/表征男性骨质疏松症的（表观）遗传变异（项目1-3）。 PPG有三个支持核心：A）管理核心; B）临床核心;和C）生物统计学和 生物信息学核心。每个核心服务于所有三个项目和/或其他核心。 识别（epi）基因/环境因素及其在人体BMD变化中的体内功能机制， 特别是对男性来说，这是必要的和重要的：1）获得对基本分子的全面了解， 和骨质疏松症风险的环境机制，2）发现新的途径和药物 治疗治愈的目标; 3）识别（表）遗传易感个体，以便未来的预防和 干预可以针对并基于个体的特定（epi-）基因型。 PPG有望为其创新开辟新天地，这是一个开创性的例子， 其他复杂疾病的类似研究。所产生的数据将是非常宝贵的老龄化和医疗领域， 本项目所研究的细胞、表型和分子生物学数据具有重要意义和相关性。

Overall Abstract Osteoporosis is mainly characterized by low bone mineral density (BMD) and its risk later in life can be most powerfully predicted by peak BMD achieved at ages 20-40. Although women have higher risk to osteoporosis, men suffer much higher morbidity and mortality rates following osteoporotic fractures. The (epi-)genetic factors underlying the majority of the BMD heritability (>85%) (especially those sex-specific ones) are largely unknown mainly due to the limitation of the technology and approaches used. Studies focusing on male osteoporosis are rare. Our General Hypothesis is that: while individual omics studies (genome/transcriptome/epigenome) are useful, integrative trans-omics analyses of multi-omics data will be much more productive and more powerful, in not only identifying novel risk (epi-)genes/variants, but also most importantly illuminating their functions in vivo in humans. The Overall Goal of this U19 program project (PPG) is to most comprehensively identify/characterize (epi- )genes/environmental factors and their functional mechanisms for male osteoporosis risk. We will pioneer a comprehensive and novel approach by investigating osteoporosis risk factors simultaneously at the genome- (DNA, Proj 1), transcriptome- (mRNA and miRNA, Proj 2), and epigenome- (DNA methylation, Proj 3) levels in males, while considering environmental factors (Proj 1-3). We will assess sex/ethnicity/population specificity of the identified (epi-)genes (Proj 1-3). Furthermore, we will perform in-depth functional studies (as exemplified in Proj 3) for detailed molecular mechanisms and functional confirmation of specific novel osteoporosis susceptibility genes/variants to be discovered. Particularly, in addition to the state-of-the-art analyses of individual omics data in Proj 1-3 respectively, we will go beyond the horizon to develop/apply innovative analytical approaches (Core C) to characterize interactions within and across different omics (such as interactions for miRNA-methylation, and regulation of mRNA by DNA variants and by miRNA/methylation). We will (in Core C) innovatively integrate such interactions across various -omics to identify/characterize (epi-)genetic variants for male osteoporosis (Proj 1-3). The PPG has three supporting cores: A) Administrative Core; B) Clinical Core; and C) Biostatistics and Bioinformatics Core. Each core serves all the three projects and/or the other cores. Identifying (epi)genes/environmental factors AND their in vivo functional mechanisms for human BMD variation, especially for men, is necessary and important for 1) gaining comprehensive insights into the fundamental molecular and environmental mechanisms underlying risk of osteoporosis, 2) discovering novel pathways and druggable targets for therapeutic cures; 3) identifying (epi-)genetically susceptible individuals, so that future preventions and interventions can be targeted to and based on individuals’ specific (epi-)genotypes. This PPG is expected to break new ground for its innovation, which serves as a pioneering example to stimulate similar studies of other complex diseases. The data generated will be invaluable for aging and medical fields for which the cells studied, phenotype and molecular data collected in this project are significant and relevant.