In silico identification of population-specific disease pathways

项目总结/摘要 阿尔茨海默病（AD）具有复杂的遗传方式，且目前的综合疗效良好 据估计，复制的迟发性AD遗传风险位点占其遗传风险的不到40%。有 目前还没有治愈这种影响约500万美国人的毁灭性神经退行性疾病的方法， 目前的治疗只能改善症状。因此，获得一个 更好地了解与疾病发展有关的每一个遗传因素， 特别是在非洲裔美国人等代表性不足的少数民族中， 为治疗和可能的预防性干预提供更好的信息设计。重要的是，大多数基因 AD的研究主要利用欧洲血统的受试者进行，但AD是欧洲血统的两倍。 在非裔美国人中很普遍与此同时，针对非裔美国人AD的研究表明， 与欧洲血统受试者中确定的AD风险变体不同。鉴于这些差异， 该研究的目的是（1）确定特定的生物学途径，以及它们的基因和遗传学特征。 可能影响非裔美国人与非裔美国人受试者AD发展差异的变异 欧洲血统，通过使用预先存在的全基因组实施基因集富集范式， 关联研究（GWAS）数据集特定于这两个人群，（2）以确定是否额外的 通过使用现有的整个外显子组的结果，可以发现它们的基因和遗传变体 序列数据集该项目的目标是整合信息， 治疗和可能的预防干预措施的设计，这可能是针对非洲的AD- 美国人

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) has a complex mode of inheritance, and the combined effect of the now well replicated late-onset AD genetic risk loci are estimated to account for less than 40% of its genetic risk. There is no cure yet for this devastating neurodegenerative disease that affects approximately 5 million Americans, and the current treatments are only capable of ameliorating the symptoms. Therefore, it is imperative to gain a better understanding of each of the genetics factors that are linked to the development of the disease, especially in underrepresented minorities such as African-Americans, with the goal of unifying this information into better informed designs for therapies and possibly preventive interventions. Importantly, most genetic studies of AD have been conducted utilizing subjects primarily of European descent, yet AD is twice as prevalent in African-Americans. Meanwhile, studies addressing AD in African-Americans have revealed different AD risk variants from those identified in subjects of European descent. Given these disparities, the goals of the proposed study are to (1) identify specific biological pathways, and their genes and genetic variants that may impact the development of AD differentially in African-Americans versus subjects of European descent, by implementing a gene-set enrichment paradigm using pre-existing genome-wide association study (GWAS) datasets specific to these two populations, and (2) to determine if additional pathways, and their genes and genetic variants can be discovered by using results from existing whole exome sequence datasets. This project has the goal of integrating information that could lead to better informed designs for therapies and possibly preventive interventions, which could potentially be tailored to AD in African- Americans.