Genomic determinants of sleep traits as risk and protective factors for Alzheimer's disease
睡眠特征的基因组决定因素作为阿尔茨海默病的风险和保护因素
基本信息
- 批准号:10453007
- 负责人:
- 金额:$ 19.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Abeta synthesisAlgorithmsAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease riskAmyloidBioinformaticsBrainBrain regionCandidate Disease GeneCerebrospinal FluidClinicalComplexComputer softwareDataData AnalysesData SetDetectionDevelopmentDiseaseDisease OutcomeDisease ProgressionEtiologyFutureGene ExpressionGenesGeneticGenetic DiseasesGenetic TranscriptionGenomicsHabitsHeterogeneityImpaired cognitionInterventionLegLife StyleLightLinkage DisequilibriumMendelian randomizationMethodsMolecularMovement DisordersNeurodegenerative DisordersNeurofibrillary TanglesObservational StudyObstructive Sleep ApneaOnset of illnessOutcomeParticipantPeriodicityPharmaceutical PreparationsPhenotypeProductionRNARiskRisk FactorsSamplingSenile PlaquesSleepSleep DisordersSleep disturbancesSleeplessnessSynapsesTestingTimeUnited StatesVariantamyloid formationanalytical methodbasebiobankcausal variantcohortdesigndisorder riskeffective therapyepidemiology studygenetic associationgenetic variantgenome wide association studygenome-widegenomic dataimprovedinnovationinstrumentmachine learning algorithmmachine learning methodmodifiable riskpreventprotective factorsstatisticssymptomatic improvementtau Proteinstraittranscriptometranscriptomics
项目摘要
PROJECT SUMMARY
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the United States and there are
no effective treatments or cure. The detection of modifiable protective or risk factors can improve the possibility
of intervention through life-style habits focused to reduce the disease risk or elevate disease protection. Sleep
disorders and disturbances have recently been recognized as risk factors for AD according to evidence from
epidemiological studies as well as associations with specific AD neuropathological hallmarks such as plaques
and tangles in the brain. However, the causal relationship between sleep disorders and disturbances and AD
has not been well established.
In this secondary data analysis proposal, we aim to study the causal effects of sleep traits on AD using
large publicly available genomics datasets including the UK Biobank (UKB), the AD Genetic Consortium
(ADGC), and others. We will use a bioinformatics workflow consisting of innovative analytical methods
designed to shed light on the causal relationship and identify specific genomics factors involved. The project
will be carried out as follows:
1) We will leverage large-scale genome-wide association studies (GWAS) conducted on sleep traits to
prioritize genes using a method (transcriptome-wide association study - TWAS) capable of detecting
phenotype-associated genes under genetic control and simultaneously related to changes in gene
expression. Then, AD RNA profiling studies will be analyzed using pseudotime algorithms, extracting latent
temporal information and ordering the samples according to disease progression. Genes identified in this
step (showing a high correlation with the disease progression and previously detected in the TWAS) will be
further investigated by Mendelian randomization to assess the causal relationship between sleep traits
(exposure) and AD (outcome).
2) A second independent analysis will be conducted by Mendelian randomization, prioritizing variants by
statistical significance from the large scale GWAS conducted on sleep traits and assessing the causal
relationship with AD. Additionally, a recently developed algorithm (latent causal variable method) will be
applied as well to detect causal relationships between sleep traits and AD.
This analytical workflow and the large size of the cohorts included will provide us with the statistical power to
identify modifiable risk and protective factors to demonstrate a causal relationship with AD.
项目摘要
阿尔茨海默病(AD)是美国最普遍的神经退行性疾病,
没有有效的治疗或治愈。检测可改变的保护性或危险因素可以提高
通过生活方式习惯进行干预,重点是降低疾病风险或提高疾病保护。睡眠
根据来自以下的证据,疾病和紊乱最近被认为是AD的危险因素:
流行病学研究以及与特定AD神经病理学标志(如斑块)的相关性
和大脑中的缠结。然而,睡眠障碍和干扰与AD之间的因果关系
这一点尚未得到很好的确立。
在这个二级数据分析提案中,我们的目标是研究睡眠特征对AD的因果影响,
大型公开可用的基因组学数据集,包括英国生物银行(UKB),AD遗传联盟
(ADGC)和其他。我们将使用由创新分析方法组成的生物信息学工作流程
旨在阐明因果关系并确定所涉及的特定基因组学因素。项目
将按以下方式进行:
1)我们将利用对睡眠特征进行的大规模全基因组关联研究(GWAS),
使用能够检测的方法(全转录组关联研究-TWAS)对基因进行优先排序
受遗传控制的表型相关基因,同时与基因的变化有关
表情然后,AD RNA谱研究将使用伪时间算法进行分析,提取潜在的
时间信息和根据疾病进展对样本进行排序。在此过程中发现的基因
步骤(显示与疾病进展的高度相关性,并且先前在TWAS中检测到)将是
通过孟德尔随机化进一步研究,以评估睡眠特征之间的因果关系,
(暴露)和AD(结果)。
2)将通过孟德尔随机化进行第二次独立分析,通过以下方式优先考虑变体:
对睡眠特征进行的大规模GWAS和评估因果关系的统计学显著性
与AD的关系此外,最近开发的算法(潜在因果变量方法)将被
也适用于检测睡眠特征和AD之间的因果关系。
这种分析工作流程和所包括的大规模队列将为我们提供统计能力,
确定可改变的风险和保护因素,以证明与AD的因果关系。
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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Ignazio Stefano Piras其他文献
Genetic history of some western Mediterranean human isolates through mtDNA HVR1 polymorphisms
- DOI:
10.1007/s10038-005-0324-y - 发表时间:
2006-01-01 - 期刊:
- 影响因子:2.500
- 作者:
Alessandra Falchi;Laurianne Giovannoni;Carla Maria Calo;Ignazio Stefano Piras;Pedro Moral;Giorgio Paoli;Giuseppe Vona;Laurent Varesi - 通讯作者:
Laurent Varesi
Y-chromosome 10 locus short tandem repeat haplotypes in a population sample from Sicily Italy.
意大利西西里岛人口样本中 Y 染色体 10 位点短串联重复单倍型。
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:1.5
- 作者:
Maria Elena Ghiani;Ignazio Stefano Piras;R. John Mitchell;G. Vona - 通讯作者:
G. Vona
Population genetic data on four STR loci, PAI (CA)<sub><em>n</em></sub>, GpIIIa (CT)<sub><em>n</em></sub>, PLAT (TG)<sub>14</sub> (CA)<sub>12</sub>, and NOS2A (CCTTT)<sub><em>n</em></sub>, in Mediterranean populations
- DOI:
10.1016/j.legalmed.2007.01.001 - 发表时间:
2007-07-01 - 期刊:
- 影响因子:
- 作者:
Alessandra Falchi;Ignazio Stefano Piras;Laurianne Giovannoni;Pedro Moral;Giuseppe Vona;Laurent Varesi - 通讯作者:
Laurent Varesi
Ignazio Stefano Piras的其他文献
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{{ truncateString('Ignazio Stefano Piras', 18)}}的其他基金
Identification of novel blood-based biomarkers of Alzheimer's Disease by pseudotime analysis
通过伪时间分析鉴定阿尔茨海默病的新型血液生物标志物
- 批准号:
10431743 - 财政年份:2022
- 资助金额:
$ 19.2万 - 项目类别:
Transcriptomic assessment of pathology in PD with dementia and dementia with Lewy Bodies using iPSC neurons and brain tissue of the same individuals
使用同一个体的 iPSC 神经元和脑组织对帕金森病痴呆和路易体痴呆进行病理学转录组评估
- 批准号:
10511261 - 财政年份:2022
- 资助金额:
$ 19.2万 - 项目类别:
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