Elucidating Shared Risk of Brain Arteriolosclerosis and Related Pathologies with Multiple 'omics Modalities

通过多种组学模式阐明脑动脉硬化及相关病理的共同风险

• 批准号: 10759365
• 负责人: Lincoln Shade
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-08 至 2025-07-07
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759365
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Architecture; Autopsy; Bioinformatics; Biological; Biological Assay; Brain; Brain Pathology; Cells; Cerebrovascular Disorders; Cerebrovascular system; Cessation of life; Chromosomes; Clinical; Clinical Research; Cognitive; Complex; DNA Methylation; Data; Data Set; Dementia; Development; Diabetes Mellitus; Disease; Epidemiologist; Fellowship; Functional disorder; Gene Expression; Generations; Genetic; Genetic Risk; Genetic study; Genomics; Genotype; Hypertension; Impaired cognition; Individual; Internet; Knowledge; Memory; Mentors; Methods; Methylation; Modality; Molecular; Multiomic Data; Outcome; Participant; Pathologic; Pathology; Pathway interactions; Phenotype; Pilot Projects; Prefrontal Cortex; Preparation; Process; Research; Research Personnel; Resources; Risk; Risk Factors; Sampling; Source; Statistical Methods; Testing; Training Programs; Translating; United States National Institutes of Health; Update; aged; arteriole; brain arteriolosclerosis; career; case control; cell type; clinical risk; cohort; comorbidity; design; endophenotype; experience; functional genomics; genetic association; genetic risk factor; genome wide association study; genome-wide; hippocampal sclerosis; human old age (65+); insight; molecular phenotype; multidisciplinary; multiple omics; neuroimaging; neuropathology; new therapeutic target; recruit; religious order study; risk sharing; risk variant; skills; therapeutic target; trait; translational genomics

Abstract Brain arteriolosclerosis (B-ASC) is a cerebrovascular disease characterized by pathological thickening of the arterioles in the brain. Non-Alzheimer’s disease brain pathologies, including B-ASC, are increasingly recognized as important contributors to cognitive decline in aged individuals. In autopsy cohorts, B-ASC is found in over 50% of participants aged eighty years or older at death. B-ASC is associated with multiple other neuropathologies, including hippocampal sclerosis. Despite its clinical importance, the pathophysiology of brain arteriolosclerosis and its mechanistic relationship to other pathologies are not well understood. We have aggregated and harmonized genotype and autopsy data between four high-quality neuropathology cohorts: the National Alzheimer’s Coordinating Center (NACC), the Religious Orders Study and the Memory and Aging Project (ROSMAP), the Adult Changes in Thought Study (ACT), and the Alzheimer’s Disease Neuroimaging Initiative Neuropathology Cohort (ADNI). In preliminary genetic association and functional genomic studies using NACC participants, we identified multiple B-ASC risk loci that replicated in at least one independent cohort and established a framework for genetic studies of neuropathological endophenotypes (NPE). In Aim 1, we hypothesize that analyses employing gene expression and DNA methylation will further characterize genomic risk factors for B-ASC pathology. We will investigate the relationship between B-ASC, gene expression, and DNA methylation in the dorsolateral prefrontal cortex using ROSMAP. These analyses will be followed by computational approaches that will estimate the contribution of different cell types and predict gene expression from genotype data in other cohorts. In Aim 2, we hypothesize that B-ASC shares genomic risk with associated NPE. We will first use our established analytic pipeline to perform genetic association studies of NPE comorbid with B-ASC. We will then use statistical methods to quantify and localize shared genetic risk between B-ASC and other NPE. Findings from these studies will provide a rigorous characterization of B-ASC risk factors and relevant biological pathways. Our cross-trait analyses will help clarify B-ASC’s place in the complex web of mixed brain pathologies common in aged individuals. The mentors and collaborators I have recruited comprise an experienced and multidisciplinary team that includes two biostatisticians, a genetic epidemiologist, and an experimental neuropathologist. This NIH F30 fellowship will provide the requisite experience, knowledge, and skills necessary as preparation to the next stage in my career as a clinical researcher.

摘要 脑动脉硬化症(B-ASC)是一种以脑血管病变增厚为特征的脑血管疾病 大脑中的小动脉。包括B-ASC在内的非阿尔茨海默病脑部病变越来越多 被认为是老年人认知能力下降的重要因素。在尸检队列中，B-ASC是 在死亡时80岁或以上的参与者中发现了超过50%的人。B-ASC与多个其他 神经病理包括海马区硬化症。尽管临床上很重要，但大脑的病理生理学 小动脉硬化及其与其他病理机制的关系尚不清楚。我们有 四个高质量神经病理队列之间的聚合和协调的基因型和尸检数据： 国家阿尔茨海默氏症协调中心(NACC)、宗教秩序研究和记忆与衰老 项目(ROSMAP)、成人思维变化研究(ACT)和阿尔茨海默病神经成像 主动神经病理队列(ADNI)。在初步的遗传关联和功能基因组研究中 利用NACC参与者，我们确定了至少一个独立的复制的多个B-ASC风险基因座 并建立了神经病理内表型(NPE)的遗传学研究框架。在目标1中， 我们假设，使用基因表达和DNA甲基化的分析将进一步表征 B-ASC病理的基因组危险因素。我们将探讨B-ASC与基因的关系 ROSMAP在前额叶背外侧皮质中的表达和DNA甲基化。这些分析将是 然后是计算方法，估计不同细胞类型的贡献并预测基因 来自其他队列中的基因数据的表达。在目标2中，我们假设B-ASC与 关联NPE。我们将首先使用我们建立的分析管道来进行遗传关联研究 NPE与B-ASC并存。然后，我们将使用统计方法来量化和定位共同的遗传风险 B-ASC和其他NPE之间的差异。这些研究的发现将为B-ASC提供严格的特征 风险因素和相关的生物途径。我们的跨性状分析将有助于澄清B-ASC在 老年人中常见的混合脑部病变的复杂网络。我的导师和合作者 招聘人员包括一支经验丰富的多学科团队，其中包括两名生物统计学家、一名遗传学家 流行病学家和实验性神经病理学家。NIH F30奖学金将提供必要的 经验、知识和技能，为我作为临床医生的下一阶段做准备 研究员。