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
基本信息
- 批准号:10667461
- 负责人:
- 金额:$ 112.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAddressAffectAgeAge of OnsetAlzheimer&aposs DiseaseAlzheimer&aposs disease riskBlood VesselsCardiovascular DiseasesCardiovascular systemCaribbean HispanicCategoriesCognitiveCollectionDataData SetDementiaDevelopmentDiseaseDisparateEarly Onset Alzheimer DiseaseEarly identificationElderlyEthnic PopulationEtiologyFailureFamilyFrequenciesGenesGeneticGenetic DiseasesGenetic VariationGenomeGenomic approachGenomicsGenotypeHeritabilityImpairmentIndividualInfrastructureInheritance PatternsInvestigationJointsLanguageLinkMemoryMental DepressionMethodsMinority GroupsMolecularMutationNeurocognitiveNeuropsychologyNot Hispanic or LatinoParticipantPathway AnalysisPathway interactionsPhenotypeProtocols documentationRaceResearchResourcesRiskRoleSamplingSymptomsTechnologyUniversitiesVariantVisuospatialWashingtonadmixture mappingadvanced analyticsanalytical methodcognitive controlcohortcomorbidityearly onsetendophenotypeexperimental studygenetic architecturegenetic linkage analysisgenetic risk factorgenetic variantgenome resourcegenome sequencinggenomic dataimprovedmemberneuropsychiatrynew therapeutic targetnovelnovel therapeuticsphenomepolygenic risk scorepresenilin-1presenilin-2racial populationrisk variantsegregationsextraitvascular risk factorwhole genome
项目摘要
PROJECT SUMMARY
Genomic studies of Alzheimer's disease (AD) have primarily focused on non-Hispanic White (NHW) participants
affected by the late-onset form of the disease (LOAD; onset age: >65), or the study of early onset AD (EOAD;
onset age <=65) cases from families showing Mendelian inheritance patterns associated with mutations in the
APP, PSEN1 and PSEN2 genes. However, mutations in these three genes explain ~10% of EOAD cases. There
are no large-scale efforts to collect and study EOAD cases not explained by these genes, despite the fact that
this unexplained EOAD category accounts for ~90% of cases. The few smaller studies that have been conducted
suggest that the genetic architecture of EOAD overlaps with the late-onset form only partially. Thus, studying
EOAD in subjects without APP, PSEN1 and PSEN2 mutations is a critical gap that provides a unique opportunity
for discovering novel therapeutic targets and molecular pathways.
To address this issue we aim to identify additional EOAD-associated variants through a large-scale whole-
genome sequencing (WGS) study of unexplained EOAD. We will include cases from several well-established
AD cohorts including the Resource for Early-onset Alzheimer Disease Research (READR), the Knight-ADRC at
Washington University, the Alzheimer's Disease Genetics Consortium (ADGC), and others. Generating and
harmonizing a dataset of 200 non-Hispanic White (NHW) and Caribbean Hispanic (CH) multiplex EOAD families,
over 4,000 EOAD singletons and over 13,000 unrelated, cognitive controls, all with WGS, this project will yield
the largest EOAD genomics dataset to-date, improving statistical power for variant identification and allowing us
to assess the impact of specific factors such as APOE genotype, vascular risk factors, and neuropsychiatric
comorbidities. The inclusion of a large set of CH families and singletons will allow the examination of EOAD risk
in a significantly understudied but fast-growing minority population. Analyses will comprise both linkage and
association-based approaches, analyses of polygenic and ancestry effects, and a thorough examination of
neurocognitive, neuropsychiatric and cardiovascular endophenotypes. We expect that when successfully
completed, this study will point to novel genetic contributors to EOAD, shed light on the mechanisms of AD and
facilitate the development of novel therapeutics.
Sampling, phenotyping and sequencing analysis protocols will be complementary to and compatible with the
existing LOAD genomics resources, such as the Alzheimer Disease Sequencing Project (ADSP) and related
studies. This phenotypic and genomic consistency, together with the use of existing AD infrastructure
(NIAGADS), allows for immediate integration with the leading efforts on LOAD, enabling rapid large-scale
investigation of a variety of additional critical AD genomics hypotheses.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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:
$ 112.39万 - 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:
$ 112.39万 - 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:
$ 112.39万 - 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:
$ 112.39万 - 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:
$ 112.39万 - 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:
$ 112.39万 - 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:
$ 112.39万 - 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:
$ 112.39万 - 项目类别:
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
- 批准号:
9194817 - 财政年份:2016
- 资助金额:
$ 112.39万 - 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:
$ 112.39万 - 项目类别:
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