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

鉴定与西班牙裔人群中阿尔茨海默病进展相关的内表型

基本信息

  • 批准号:
    10448860
  • 负责人:
  • 金额:
    $ 40.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

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.
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,统称为 阿尔茨海默病和相关痴呆(ADRD)。ADRD损害个人正常运作的能力,并 构成了一个重大的世界性公共卫生问题,没有有效的治疗方法。ADRDS影响人们 在所有种族中,但拉美裔美国人尤其受到它的影响。拉美裔美国人罹患癌症的风险是后者的1.5倍 ADRD比非西班牙裔白人更多。ADRD是复杂的表型,其诊断通常需要侵入性 措施。因此,识别可靠的非侵入性早期ADRD生物标志物是为更好地提供 早期诊断,指导患者治疗。为了实现这一目标,该项目旨在识别新的非侵入性 马拉开波老龄化研究中现有的一组拉美裔美国人的内表型分析 住在委内瑞拉马拉开波。MAS始于1998年,对纵向遗传进行了调查, 可能导致ADRD流行的环境和社会经济因素。MAS项目 目前包括约5,000名老年人(年龄55岁)和415名遗传相关参与者的子集 广泛的表型,包括完整的核磁共振脑成像和全面认知 评估ADRD患病率较高(6.8%)。使用基于家族的设计,我们计算了遗传因素 占疾病风险变异性的67%。为了确定新的ADRD和认知衰退的内表型, 我们将构建一个可供1000名MAS参与者使用的RNAseq文库,并应用我们的ERV(内表型排名 值)方法。我们将MAS参与者分为两个相等的子集,每个子集500个,用于发现和复制 套装分别来自委内瑞拉的圣罗莎和圣卢西亚社区。发现子集 将包括DSM-IVR标准定义的122例ADRD病例,更重要的是,一组243例1至5级 目前未患痴呆症的亲生亲属。我们将把它们与135套进行对比 未受影响的个体(缺乏ADRD的已知亲属)以确定基因表达的内表型。 这些群体之间的差异只能是由于ADRD风险和 通过ERV方法确定的内表型,考虑了诸如年龄、发病年龄、性别等协变量 和APOE基因座状态。在发现集合中检测到的内表型将被确认为集合中的生物标志物 在250个ADRD病例和250个未受影响的对照中,使用线性混合模型并随后通过 科学文献综述。我们使用我们大脑遗传学的现有数据来测试我们方法的有效性 结构研究,我们发现已知的候选基因的表达和 痴呆症风险。我们将ERV方法应用于MAS基因表达数据,并预测它将执行 更好的是,MAS人群表现出更高的ADRD患病率。这个项目将作为一个步骤 斯通对西班牙裔ADRD易感性的进一步表征和我们的方法可能会识别潜在的 新的候选基因,赋予或保护该人群中的ADRD风险。这一预期的结果是 科学提案将成为未来科学提案的必要种子,这将进一步扩大我们的发现。

项目成果

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