Personalized genetic profiles of risk and resilience in Alzheimer's and vascular diseases
Personalized genetic profiles of risk and resilience in Alzheimer's and vascular diseases
批准号:
10338056
负责人:
ALEXANDER M KULMINSKI
金额:
$76.06万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-02-15 至 2025-01-31
关键词:
AddressAffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAlzheimer’s disease biomarkerBioinformaticsBiologicalBiologyBirthBlood GlucoseBlood PressureBlood VesselsBody mass indexCardiovascular DiseasesCharacteristicsCholesterolComplexDataDevelopmentDiastolic blood pressureDiseaseEducationEnvironmental ExposureEpigenetic ProcessEthnic OriginGene ExpressionGenesGeneticGenetic Predisposition to DiseaseGenetic TranscriptionGenotypeGoalsHaplotypesHeterogeneityHigh Density LipoproteinsHypertensionIndividualInterventionLifeLinkLinkage DisequilibriumLipidsLow-Density LipoproteinsMediationMeta-AnalysisMethodsMethylationMolecular AnalysisMolecular ProfilingNon-Insulin-Dependent Diabetes MellitusOnset of illnessPathway interactionsPatternPersonsPhysical activityProxyQuantitative Trait LociRaceResearchResourcesRiskRisk FactorsRoleSamplingSmokingStatistical MethodsStrokeStructureTriglyceridesVariantVascular DiseasesWorkage relatedbasecognitive performancecohortdensitydisease phenotypeexomegenetic associationgenetic variantgenome wide association studygenome-wide analysisimprovedindexinginsightlifestyle factorslipoprotein cholesterolnon-geneticnovelpersonalized interventionpersonalized therapeuticpolygenic risk scoreprecision geneticsprotective factorsrare variantreproductiveresiliencesexstatisticstraitvascular risk factor
中文摘要
先前的研究和2018年NIA-阿尔茨海默氏症协会框架强调,对
阿尔茨海默病(AD)需要复杂的生物学和异质性才能开发出有效的
可以根据个人独特的风险特征量身定做的干预措施。这些配置文件很可能是
阿尔茨海默病的许多遗传和非遗传风险和保护因素的相互作用,包括血管风险因素
起源,这是很难解开的。新出现的证据还表明,ADS和血管
疾病往往聚集在一起。该项目解决了PAR-17-054关于解开纠缠的目标
遗传和阿尔茨海默病/血管危险因素在阿尔茨海默病风险和复原力中的异质性交互作用,包括
年龄效应,通过利用现有资源和参与将会改善的活动
统计学上的力量。我们的方法,结合了全基因组关联研究的彻底方法和
在大样本中类似候选方法的严谨性建立在:(I)进化的核心原则
阿尔茨海默病遗传学中的生物学和其他生殖后生活的年龄相关特征,这涉及到
这些性状的遗传易感性具有内在的异质性,(Ii)从先前的研究中获得的见解
这些特征(包括我们自己的工作),以及(Iii)我们的大规模研究证明其
利用现有资源大幅提高电力的重要性、可行性和潜力。这
研究有助于更好地了解先前研究的严谨性中的弱点,并提供
令人信服的证据表明,我们的方法是推动在以下方面取得进展的自然和关键战略
剖析AD与血管性状的内在异质性机制。我们的目标是确定
风险和复原力的个人化(即更加同质、特定于群体)单基因/多基因概况
AD和血管疾病在疾病特异性和多效性背景下的优先基因座杠杆作用
来自本项目和以前计划的以AD为中心的多效性荟萃分析的信息
我们和其他研究小组的分析,并确定AD风险和其他因素在这些方面的作用
配置文件。我们将解决以下具体目标:目标1.确定AD的特定和多效性基因座
以及来自新的分析和现有研究的血管特征。目标2.剖析异构性
分子特征的分析定义为连接不平衡结构的差异。
受影响和未受影响的受试者。目的3.确定阿尔茨海默病患者的个性化基因图谱
多效性风险和韧性。目的4.从已识别的SNPs中表征SNPs的功能作用
这些SNPs的单/多基因变异和基因的生物学作用。描述转录的特征
利用个体水平的基因表达、表观遗传学数据和汇总统计研究SNPs的途径
从可获得的表达和甲基化数量性状基因座研究。
英文摘要
Prior research and the 2018 NIA-Alzheimer’s-Association framework emphasize that novel insights into
the complex biology and heterogeneity of Alzheimer’s disease (AD) are needed to develop efficient
interventions that can be tailored to persons’ unique risk profiles. These profiles are likely a result of an
interplay of many genetic and non-genetic risk and protective factors for AD, including those of vascular
origin, which are difficult to disentangle. Emerging evidence suggests also that ADs and vascular
diseases tend to cluster together. This project addresses an objective of PAR-17-054 on disentangling
heterogeneous interactions of genetic and AD/vascular risk factors in risk and resilience to AD, including
age-specific effects, by leveraging existing resources and engaging in activities that will improve
statistical power. Our approach, combining thorough methods of genome-wide association studies and
the rigor of the candidate-like methods in large samples, is built on: (i) core principles of evolutionary
biology in genetics of AD and other age-related traits characteristic of post-reproductive life, which deals
with an inherent heterogeneity in genetic predisposition to such traits, (ii) insights from prior studies of
such traits (including our own work), and (iii) promising results of our large-scale studies proving its
significance, feasibility, and potential to substantially improve power using the existing resources. This
research contributed to better understanding of weaknesses in the rigor of prior studies and provided
compelling evidence that our approach is a natural and critical strategy to advance the progress in
dissecting the inherently heterogeneous mechanisms of AD and vascular traits. The goal is to identify
personalized (i.e., more homogeneous, group-specific) mono/polygenic profiles of risks and resilience
to AD and vascular diseases in the disease-specific and pleiotropic contexts in prioritized loci leveraging
information from the AD-centered pleiotropic meta-analysis planned in this project and previous
analyses by our and other research groups, and identify the role of AD risk and other factors in these
profiles. We will address the following specific aims: Aim 1. Identify specific and pleiotropic loci for AD
and vascular traits from new analyses and the existing studies. Aim 2. Dissect heterogeneity leveraging
the analysis of molecular signatures defined as differences in linkage disequilibrium structures in
affected and unaffected subjects. Aim 3. Identify personalized genetic profiles of AD-specific and
pleiotropic risks and resilience. Aim 4. Characterize the functional roles of SNPs from the identified
mono/polygenic variants and biological roles of genes for these SNPs. Characterize transcription
pathways for SNPs using individual-level gene expression and epigenetic data and summary statistics
from the available expression and methylation quantitative trait loci studies.
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会议论文
Dissecting genetic and non-genetic heterogeneity in predisposition to Alzheimer's disease and vascular traits in pleiotropic context
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批准号:10398945
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项目类别:
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资助金额:$56.45万
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财政年份:2020
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负责人:ALEXANDER M KULMINSKI
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依托单位:
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资助金额:$56.39万
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依托单位:
Genetics of aging, health and longevity: focus on regulatory mechanisms and functional variants connecting aging and Alzheimer's disease
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批准号:10399467
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资助金额:$49.59万
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批准号:10118695
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资助金额:$56.45万
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财政年份:2020
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负责人:ALEXANDER M KULMINSKI
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依托单位:
Genetics of aging, health and longevity: focus on regulatory mechanisms and functional variants connecting aging and Alzheimer's disease
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批准号:10618201
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资助金额:$49.04万
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财政年份:2020
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依托单位:
Dissecting genetic and non-genetic heterogeneity in predisposition to Alzheimer's disease and vascular traits in pleiotropic context
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批准号:10164704
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项目类别:
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资助金额:$56.45万
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财政年份:2020
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负责人:ALEXANDER M KULMINSKI
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依托单位:
Genetics of aging, health and longevity: focus on regulatory mechanisms and functional variants connecting aging and Alzheimer's disease
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批准号:10118665
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项目类别:
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资助金额:$50.3万
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财政年份:2020
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负责人:ALEXANDER M KULMINSKI
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依托单位:
ApoE2 and protective molecular signatures in Alzheimer's disease and aging
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批准号:10425329
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项目类别:
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资助金额:$76.72万
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财政年份:2018
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负责人:ALEXANDER M KULMINSKI
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依托单位:
ApoE2 and protective molecular signatures in Alzheimer's disease and aging
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批准号:10170216
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资助金额:$76.72万
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财政年份:2018
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负责人:ALEXANDER M KULMINSKI
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依托单位:
Life Course and Genetic and Non-genetic Factors in Health and Survival
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财政年份:2015
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依托单位:
Molecular signatures of health and life span disparities between whites and African-Americans in the APOE region
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依托单位:
Life Course and Genetic and Non-genetic Factors in Health and Survival
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批准号:9064049
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项目类别:
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资助金额:$43.59万
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财政年份:2015
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负责人:ALEXANDER M KULMINSKI
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依托单位:
GENES AND OTHER FACTORS AFFECTING HEALTH TRAITS: EFFECTS O NAGING AND LIFESPAN
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项目类别:
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资助金额:$40.45万
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财政年份:--
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负责人:ALEXANDER M KULMINSKI
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依托单位:
GENES AND OTHER FACTORS AFFECTING HEALTH TRAITS: EFFECTS O NAGING AND LIFESPAN
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项目类别:
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资助金额:$39.68万
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财政年份:--
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负责人:ALEXANDER M KULMINSKI
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依托单位:
GENES AND OTHER FACTORS AFFECTING HEALTH TRAITS: EFFECTS O NAGING AND LIFESPAN
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批准号:9262862
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项目类别:
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资助金额:$40.53万
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财政年份:--
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负责人:ALEXANDER M KULMINSKI
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依托单位:
海外基金