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:9811242
- 负责人:
- 金额:$ 404.84万
- 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 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAffectAgeAge of OnsetAlzheimer&aposs DiseaseAlzheimer&aposs disease riskBlood VesselsCardiovascular DiseasesCardiovascular systemCaribbean HispanicCategoriesCognitiveCollectionComorbidityDataData SetDementiaDevelopmentDiseaseElderlyEthnic groupEtiologyFailureFamilyFrequenciesGenesGeneticGenetic DiseasesGenetic VariationGenomeGenomic approachGenomicsGenotypeHeritabilityImpairmentIndividualInfrastructureInheritance PatternsInvestigationJointsLanguageLightLinkMemoryMental DepressionMethodsMinorityMolecularMutationNeurocognitiveNeuropsychologyNot Hispanic or LatinoParticipantPathway AnalysisPathway interactionsPhenotypePopulationPresenile Alzheimer DementiaProtocols documentationRaceResearchResourcesRiskRoleSamplingSymptomsTechnologyUniversitiesVariantVisuospatialWashingtonadmixture mappinganalytical methodbasecognitive controlcohortearly onsetendophenotypeexperimental studygenetic architecturegenetic linkage analysisgenetic risk factorgenetic variantgenome sequencinggenomic dataimprovedmemberneuropsychiatrynew therapeutic targetnovelnovel therapeuticsphenomepresenilin-1presenilin-2risk 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.
项目摘要
阿尔茨海默病(AD)的基因组研究主要集中在非西班牙裔白色(NHW)参与者
受疾病的晚发形式(LOAD;发病年龄:>65)影响,或早发性AD(EOAD;
发病年龄<=65岁),来自孟德尔遗传模式的家族病例,
APP、PSEN 1和PSEN 2基因。然而,这三个基因的突变解释了约10%的EOAD病例。那里
没有大规模的努力来收集和研究这些基因不能解释的EOAD病例,尽管事实上,
这种无法解释的EOAD类别约占病例的90%。已经进行的为数不多的小型研究
表明EOAD的遗传结构与迟发性形式仅部分重叠。因此,学习
无APP、PSEN 1和PSEN 2突变的受试者的EOAD是一个关键差距,提供了一个独特的机会
用于发现新的治疗靶点和分子途径。
为了解决这个问题,我们的目标是通过一个大规模的整体,
基因组测序(WGS)研究不明原因的EOAD。我们将包括来自几个成熟的案例
AD队列,包括早发性阿尔茨海默病研究资源(READR),
华盛顿大学、阿尔茨海默病遗传学联盟(ADGC)等。生成和
协调200个非西班牙裔白色(NHW)和加勒比西班牙裔(CH)多重EOAD家族的数据集,
超过4,000名EOAD单例患者和超过13,000名不相关的认知对照患者,所有患者均使用WGS,该项目将产生
迄今为止最大的EOAD基因组学数据集,提高了变异识别的统计能力,
评估特定因素的影响,如APOE基因型、血管危险因素和神经精神因素。
合并症。纳入大量CH家族和单胎患者将允许检查EOAD风险
在一个研究严重不足但快速增长的少数民族人口中。分析将包括联系和
基于关联的方法,多基因和祖先效应的分析,以及对
神经认知、神经精神和心血管内表型。我们希望当成功的时候
完成后,这项研究将指出EOAD的新遗传因素,阐明AD的机制,
促进新疗法的发展。
采样、表型分析和测序分析方案将与
现有的LOAD基因组学资源,如阿尔茨海默病测序项目(ADSP)和相关的
问题研究这种表型和基因组的一致性,以及使用现有的AD基础设施,
(NIAGADS),允许立即与LOAD上的主要工作集成,从而实现快速的大规模
研究了各种其他关键的AD基因组学假设。
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:
$ 404.84万 - 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:
$ 404.84万 - 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:
$ 404.84万 - 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:
$ 404.84万 - 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:
$ 404.84万 - 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:
$ 404.84万 - 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:
$ 404.84万 - 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:
$ 404.84万 - 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:
$ 404.84万 - 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:
$ 404.84万 - 项目类别:
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