Genetic Epidemiology of Early-Onset Alzheimers disease in Caribbean Hispanics and non-Hispanic Whites

加勒比西班牙裔和非西班牙裔白人早发性阿尔茨海默病的遗传流行病学

基本信息

项目摘要

Project Summary To further disentangle the molecular mechanisms underlying Alzheimer's disease (AD) and to foster the mapping of therapeutic targets, we propose an extreme phenotype design: a whole-genome sequencing (WGS) study of early-onset AD (EOAD) in a large set of multiply affected, well-phenotyped Caribbean Hispanic (CH) and non-Hispanic White (NHW) families. Extreme phenotype designs (e.g., early age-at-onset--AAO, fast vs. slow progressors, very high vs. very low biomarker levels, etc) increase statistical power by creating more homogeneous and genetically loaded populations, and have the potential to reveal genetic risk factors and mechanisms that are difficult to identify in more heterogeneous datasets. This is critical for clarifying AD etiology and developing more effective therapeutic targets. Early studies in AD focused on EOAD and identified a limited number of highly penetrant risk variants: APP, PSEN1, and PSEN2. These genes increase the generation and/or aggregation of the amyloid ß peptide, an observation that underlies current therapeutic strategies. However, these known mutations account for less than half of the genetic basis of EOAD. Many of the EOAD families do not carry known mutations, and among known mutation carriers AAO is often highly variable. This unexplained genetic component to EOAD represents a critical gap in our understanding of AD etiology—a gap not filled by the ongoing AD sequencing studies, which largely focus on the more heterogeneous late-onset form of AD (LOAD). Additionally, this proposal includes both Hispanic and non-Hispanic white samples. The inclusion of minority populations allows us to examine EOAD risk in an understudied but fast-growing population and to map AD risk loci that are unique to this ethnic group, giving further insight into the etiologic mechanisms underlying the disease. To accomplish these goals, we propose the following Aims: (SA1) Identification of novel genetic risk factors for EOAD by whole genome and targeted sequencing. We will perform WGS in 87 multiplex EOAD families, followed by bioinformatics annotation and prioritization based on segregation and function. Highest priority genes/regions will be validated in the family and then will become targets for custom sequencing in a set of EOAD singletons to maximize variant identification. (SA2) Putative functional loci resulting from SA1 will be validated in independent EOAD samples using custom genotyping arrays and (SA3) evaluated for generalizability to late-onset AD using existing LOAD resources such as the ADSP, ADGC, and WHICAP datasets. Finally (4), the most interesting variants will be subject to rapid, biological screening procedures to determine their molecular effects.
项目总结

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Gary Wayne Beecham其他文献

Gary Wayne Beecham的其他文献

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{{ truncateString('Gary Wayne Beecham', 18)}}的其他基金

Genetic and neuroanatomical basis of neuropsychiatric symptoms in Alzheimer's disease in populations of diverse ancestry
不同血统人群中阿尔茨海默病神经精神症状的遗传和神经解剖学基础
  • 批准号:
    10567606
  • 财政年份:
    2023
  • 资助金额:
    $ 357.86万
  • 项目类别:
Genomic Characterization of Alzheimer Disease Risk in Admixed Populations with Native American and Southern European Genetic Ancestry
美洲原住民和南欧遗传血统混合人群阿尔茨海默病风险的基因组特征
  • 批准号:
    10615046
  • 财政年份:
    2021
  • 资助金额:
    $ 357.86万
  • 项目类别:
Genomic Characterization of Alzheimer Disease Risk in Admixed Populations with Native American and Southern European Genetic Ancestry
美洲原住民和南欧遗传血统混合人群阿尔茨海默病风险的基因组特征
  • 批准号:
    10335250
  • 财政年份:
    2021
  • 资助金额:
    $ 357.86万
  • 项目类别:
Identifying the Genetic Etiology of Neuropathology for Alzheimer Disease and Related Dementias
确定阿尔茨海默病和相关痴呆症神经病理学的遗传病因
  • 批准号:
    10612832
  • 财政年份:
    2019
  • 资助金额:
    $ 357.86万
  • 项目类别:
Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes
剖析非孟德尔早发性阿尔茨海默病的基因组病因学及相关表型
  • 批准号:
    10412088
  • 财政年份:
    2019
  • 资助金额:
    $ 357.86万
  • 项目类别:
Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes
剖析非孟德尔早发性阿尔茨海默病的基因组病因学及相关表型
  • 批准号:
    10667461
  • 财政年份:
    2019
  • 资助金额:
    $ 357.86万
  • 项目类别:
Identifying the Genetic Etiology of Neuropathology for Alzheimer Disease and Related Dementias
确定阿尔茨海默病和相关痴呆症神经病理学的遗传病因
  • 批准号:
    10372972
  • 财政年份:
    2019
  • 资助金额:
    $ 357.86万
  • 项目类别:
Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes
剖析非孟德尔早发性阿尔茨海默病的基因组病因学及相关表型
  • 批准号:
    9811242
  • 财政年份:
    2019
  • 资助金额:
    $ 357.86万
  • 项目类别:
National Institute on Aging Alzheimer's Disease Family-Based Study (NIA-AD FBS)
国家老年阿尔茨海默病家庭研究研究所 (NIA-AD FBS)
  • 批准号:
    10355812
  • 财政年份:
    2017
  • 资助金额:
    $ 357.86万
  • 项目类别:
Genomic Characterization of Alzheimer's Disease Risk in the Puerto Rican Population
波多黎各人群阿尔茨海默病风险的基因组特征
  • 批准号:
    9194733
  • 财政年份:
    2016
  • 资助金额:
    $ 357.86万
  • 项目类别:

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Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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