Identification of endophenotypes associated with Alzheimer’s disease progression in Hispanic population

摘要 痴呆症是由一系列与年龄相关的神经退行性疾病引起的， 阿尔茨海默病和相关痴呆症（ADRD）。ADRD损害个体正确运作的能力， 这是一个重大的全球公共卫生问题，没有有效的治疗方法。ADRD影响人们 所有种族中，但西班牙裔受其影响尤其严重。西班牙裔患上糖尿病的风险高出1.5倍， ADRD比非西班牙裔白人。ADRD是复杂的表型，其诊断通常需要侵入性检查。 措施因此，识别可靠的非侵入性早期ADRD生物标志物是提供更好的治疗的关键主题。 早期诊断，指导治疗。为了实现这一目标，该项目旨在确定新的非侵入性 在马拉开波老龄化研究中使用转录组学分析的现有西班牙裔队列中的内表型 (MAS)住在委内瑞拉的马拉开波。MAS始于1998年，对遗传学进行了纵向调查， 环境和社会经济因素，可能有助于ADRD的患病率。MAS项目 目前包括约5000名老年人（年龄≥55岁）和415名遗传相关参与者的子集 已经被广泛的表型，包括完整的MRI脑成像和全面的认知 ADRD患病率较高（6.8%）。使用基于家族的设计，我们计算出遗传因素 占疾病风险变异的67%。为了鉴定新的ADRD和认知衰退内表型， 我们将为1000名MAS参与者构建RNASeq文库，并应用我们的ERV（Endophenotype Ranking 值）方法。我们将MAS参与者分成两个相等的子集，每个子集500个，用于发现和复制 分别来自委内瑞拉的圣罗莎和圣露西亚社区。发现子集 将包括122例由DSM-IVR标准定义的ADRD病例，更重要的是，一组243例1至5度 目前没有患痴呆症的生物学亲属。我们将它们与一组135个 未受影响的个体（缺乏已知的ADRD亲属），以鉴定基因表达内表型。 这些群体之间的差异只能是由于ADRD风险和ADRD风险之间的遗传相关性。 通过ERV方法确定的内表型，考虑到协变量，如年龄、发病年龄、性别 和APOE基因座状态。在发现集中检测到的内表型将被确认为一个集中的生物标志物 250例ADRD病例和250例未受影响的对照使用线性混合模型，随后通过 科学文献综述。我们使用来自大脑遗传学的现有数据测试了我们方法的有效性 在结构研究中，我们确定了已知候选基因的表达与 痴呆风险我们将ERV方法应用于MAS基因表达数据，并预测它将执行 甚至更好，因为MAS人群表现出更高的ADRD患病率。该项目将作为一个步骤， 进一步描述西班牙裔ADRD易感性的关键，我们的方法可能会识别出潜在的 新的候选基因，赋予或保护对ADRD的风险，在这个群体中。预期的结果是， 科学建议将是未来科学建议的必要种子，这些科学建议将进一步扩展我们的发现。

Abstract Dementia is caused by a constellation of age-associated neurodegenerative diseases collectively termed Alzheimer’s disease and related dementias (ADRD). ADRDs impair individuals' ablity to correctly function and constitutes a major worldwide public health problem, with no effective treatments available. ADRDs affect people of all ethnicities, but Hispanics are especially affected by it. Hispanics have 1.5-fold higher risk of developing ADRD than non-Hispanic whites. ADRDs are complex phenotypes and their diagnosis often requires invasive measures. Therefore, identifying reliable noninvasive early ADRD biomarkers is a key topic to provide better early diagnosis and guide patient’s treatment. Toward this goal, this project aims to identify novel non-invasive endophenotypes using transcriptomic profiling in an existing cohort of Hispanics from the Maracaibo Aging Study (MAS) living in Maracaibo, Venezuela. The MAS, begun in 1998, has surveyed longitudinally genetic, environmental, and socioeconomic elements that may contribute to ADRD prevalence. The MAS project currently includes ~5000 elderly individuals (aged ≥55 yr) and a subset of 415 genetically related participants that have been extensively phenotyped, including complete MRI brain imaging and comprehensive cognitive assessment with a high ADRD prevalence (6.8%). Using a family-based design, we calculate that genetic factors account for 67% of the variability in disease risk. To identify novel ADRD and cognitive decline endophenotypes, we will construct a RNASeq library for 1000 MAS participants, and apply our ERV (Endophenotype Ranking Value) method. We will divided MAS participants into two equal subsets of 500 each for discovery and replication sets respectively coming from Santa Rosa and Santa Lucia communities in Venezuela. The discovery subset will include 122 ADRD cases defined by DSM-IVR criteria and, more importantly, a set of 243 1st- to 5th-degree biological relatives who are not currently suffering from dementia. We will contrast them with a set of 135 unaffected individuals (lacking known relatives with ADRD) to identify gene expression endophenotypes. Differences between these groups can only occur due to genetic correlation between ADRD risk and an endophenotype as identified by the ERV method taking into account covariates such as age, age at onset, sex and APOE locus status. Endophenotypes detected in the discovery set will be confirmed as biomarkers in a set of 250 ADRD cases and 250 unaffected controls using a linear mixed model and later annotated by means of a scientific literature review. We tested our approach's validity using existing data from our Genetics of Brain Structure Study where we identified strong associations between known the expression of candidate genes’ and dementia risk. We will apply the ERV method to the MAS gene expression data and predict that it will perform even better since the MAS population manifests higher ADRD prevalence. This project will serve as a stepping stone to further characterization of ADRD predisposition in Hispanics and our approach may identify potentially novel candidate genes that confer or protect against ADRD risk in this population. The expected results of this scientific proposal will be the necessary seeds for future scientific proposals that will further extend our findings.