Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk

识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异

• 批准号: 10676499
• 负责人: Razaq Olumide Durodoye
• 金额: $ 5.27万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676499
• 关键词: Address; Affect; African American population; African ancestry; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Automobile Driving; Bioinformatics; Biological; Black Populations; Black race; Cessation of life; Committee Members; Complex; Data; Data Set; Dementia; Disease; Doctor of Philosophy; Economic Burden; Education; Elderly; Ethnic Origin; Ethnic Population; European; Frequencies; Functional disorder; Gene Frequency; Genes; Genetic; Genetic Diseases; Genetic Variation; Genetic study; Genome; Genotype; Health Sciences; Healthcare; Hispanic; Individual; Intervention; Investigation; Late Onset Alzheimer Disease; Latino; Latino Population; Low Prevalence; Medical; Memory Loss; Modeling; Modification; Neurocognitive; Neurodegenerative Disorders; Not Hispanic or Latino; Pathway interactions; Persons; Physicians; Physiological; Play; Population; Population Genetics; Population Heterogeneity; Prevalence; Race; Research; Risk; Risk Estimate; Risk Factors; Role; Scientist; Sequence Analysis; Single Nucleotide Polymorphism; Source; Statistical Data Interpretation; Statistical Distributions; Testing; Training; Training Programs; Underserved Population; United States; Universities; Variant; Work; burden of illness; clinical training; cost; dementia risk; diverse data; experience; genetic risk factor; genetic variant; genome wide association study; genomic locus; insight; lipid metabolism; marginalization; multi-ethnic; multilevel analysis; novel strategies; protective allele; racial population; risk variant; skills; therapy development; whole genome

PROJECT SUMMARY/ABSTRACT Studying genetic contributions to dementia risk from both the population-specific and trans-ancestral perspectives is vital to disease prediction, characterization, and the development of treatment interventions. Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, costs the United States an estimated $305 billion in associated costs, and affects approximately 6 million individuals nationally, and more than 24 million people globally. Apolipoprotein E (ApoE) is the strongest known genetic risk factor for LOAD. Specifically, ApoE-associated LOAD risk is driven by a risk variant of ApoE (termed ε4 or ApoE4) while ApoE- associated LOAD protection is thought to be driven by a protective variant of the gene (termed ε2 or ApoE2). The allele frequency of these alleles varies across populations, partially explaining higher LOAD prevalence in populations of African descent who carry the highest ApoE4 allele frequencies. In contrast to these findings, evidence indicates ApoE4-associated LOAD risk is significantly lower in individuals of African descent compared to other groups. This effect modification is partially driven by population-specific local ancestry that modifies the effect size of ApoE4. This observation, however, does not fully explain the reduction in effect size in African Americans. I hypothesize that genetic variants (local and global) modify ApoE4 and ApoE2 effect sizes. This proposal describes three aims to address the investigation into genetic contributions to ApoE- associated LOAD risk in multiple, diverse populations. Aim 1 will document the relationship between LOAD risk and the ApoE4 and ApoE2 alleles in the largest and most diverse dataset to be studied to date by estimating effect sizes in each of several diverse populations. Aim 2 will identify SNPs that associate with extreme ApoE4 and ApoE2 effect sizes and test whether these SNPs define specific physiological pathway association. Finally, aim 3 will evaluate the relative roles of race/ethnicity and genetic variation as modifiers of effect sizes within and between populations. As an MD/PhD candidate, I am passionate about this project as it will lead to new insights that can be used to understand, identify, and predict LOAD risk in underserved populations in the United States, especially those that experience increased LOAD burdens. The combined educational support from the Population and Quantitative Health Sciences Department and clinical training from the Medical Scientist Training Program at Case Western Reserve University will prepare me in tackling the genetic and healthcare avenues this work aims to inform. With support from these sources, and committee members with expertise in population genetics, statistical analysis, and bioinformatics, my training will provide the skills necessary to become a physician scientist versed in rigorous statistical approaches to understanding contributions to complex diseases.

项目总结/摘要 研究人群特异性和跨祖遗传对痴呆风险的遗传贡献 这些观点对于疾病预测、表征和治疗干预措施的发展至关重要。 晚发性阿尔茨海默病（LOAD）是最常见的痴呆症，花费了美国一年的时间。 估计3050亿美元的相关费用，影响全国约600万人， 全球超过2400万人。载脂蛋白E（ApoE）是已知最强的LOAD遗传风险因素。 具体而言，ApoE相关的LOAD风险由ApoE的风险变体（称为ε4或ApoE 4）驱动，而ApoE相关的LOAD风险由ApoE的风险变体（称为ε4或ApoE 4）驱动。 相关的LOAD保护被认为是由基因的保护性变体（称为ε2或ApoE 2）驱动的。 这些等位基因的等位基因频率在不同人群中不同，部分解释了LOAD的高患病率， 携带最高ApoE 4等位基因频率的非洲裔人群。与这些发现相反， 有证据表明，ApoE 4相关的LOAD风险在非洲裔个体中显著降低 与其他群体相比。这种效应的改变部分是由特定人群的当地祖先驱动的， 改变ApoE 4的效应量。然而，这一观察结果并不能完全解释效应量的减少 在非裔美国人中。我假设遗传变异（局部和整体）改变了ApoE 4和ApoE 2效应 尺寸.该提案描述了三个目标，以解决对ApoE遗传贡献的调查， 多个不同人群中的相关LOAD风险。目标1将记录LOAD风险与 以及迄今为止通过估计研究的最大、最多样化的数据集中的ApoE 4和ApoE 2等位基因 不同人群中的效应量。目标2将鉴定与极端ApoE 4相关的SNP 和ApoE 2效应大小，并测试这些SNP是否定义了特定的生理途径关联。最后， 目标3将评估种族/民族和遗传变异作为效应量修饰因子的相对作用， 和人口之间。作为一名MD/PhD候选人，我对这个项目充满热情，因为它将带来新的 可用于了解，识别和预测服务不足人群的LOAD风险的见解 美国，特别是那些经历了增加负载负担的国家。综合教育支持 来自人口和定量健康科学部的临床培训和来自医学部的临床培训。 凯斯西储大学的科学家培训计划将帮助我解决遗传问题， 这项工作旨在提供信息的医疗保健途径。在这些来源的支持下， 在群体遗传学，统计分析和生物信息学方面的专业知识，我的培训将提供技能 必须成为一名精通严格统计方法的医生科学家， 对复杂疾病的贡献。