Going from Genetic Associations to Identification of Causative Genes
从遗传关联到致病基因的识别
基本信息
- 批准号:10555812
- 负责人:
- 金额:$ 66.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAdipocytesAffectAnatomyAnimal ModelAnimalsAstrocytesBehaviorBiologicalBiological AssayBiological ModelsCRISPR/Cas technologyCandidate Disease GeneCellsChromatinChromatin LoopChromosome MappingClinicalCommunitiesComplementComplexDataDiseaseDrosophila genusDrowsinessEnhancersExcessive Daytime SleepinessFatty acid glycerol estersFishesGene ExpressionGene TargetingGenesGeneticGenomeGenomicsGenotypeGoalsHumanImageInduced pluripotent stem cell derived neuronsInvestmentsKnock-outKnowledgeLinkMagnetic Resonance ImagingMapsMedicineMesenchymal Stem CellsMethodsModelingMusNeurogliaNeuronsObesityObstructive Sleep ApneaOsteoblastsPathway interactionsPatientsPhenotypeProcessQuantitative Trait LociRNA InterferenceRNA interference screenResearchResolutionResourcesRiskRisk FactorsSamplingSeveritiesShapesSignal TransductionSiteSleepSleep Apnea SyndromesSleep FragmentationsSleep disturbancesSleeplessnessTestingTongueTransposaseValidationVariantZebrafishcandidate identificationcausal variantcell typeclinical translationcraniofacialdisorder riskdiverse dataflyfollow-upgene functiongenetic associationgenetic variantgenome wide association studygenome-widegenomic locusin silicoknock-downknockout genemultidimensional datanovelprecision medicineprogramspromotersleep behaviortraittranscriptome sequencing
项目摘要
ABSTRACT
Many studies, including analyses in this overall Program of research, have conducted genome-wide
association studies (GWAS) to identify genes and loci associated with complex disease. While a number of
genetic association signals have been uncovered, the challenge of identifying causative genes at these genetic
loci remains. As such, the goal of this Project is to move from GWAS association to identification of causal
effector genes relevant to obstructive sleep apnea (OSA) and excessive sleepiness, two key traits studied in this
Program. To fill this critical gap in evidence this Project combines state-of-the-art approaches in cell-based and
animal models. Analyses will begin by interrogating genetic loci from recent GWAS on OSA and sleepiness, and
be extended to evaluate loci from ongoing analyses, including those in Projects 01 and 03. In Aim 1, we will
conduct in silico physical `variant to gene mapping' based on our established Assay for Transposase Accessible
Chromatin sequencing (ATAC-seq) plus genome-wide promotor-focused Capture C data on relevant cell types
- osteoblasts and adipocytes (for anatomy; relevant to Project 01) and neurons and primary astrocytes (for
sleepiness; relevant to Project 03). These 3D Genomics analyses will identify the most likely causal genes and
variants by determining which candidates at implicated loci directly interact with regions of open chromatin. After
identifying likely causal genes and variants, follow-up analyses in animal models will be performed to understand
if candidate effector genes act by affecting OSA-related anatomy in mice (Aim 2) and sleep behavior reflective
of sleepiness and disturbed sleep in Drosophila and zebrafish (Aim 3). Specifically, Aim 2 will utilize the novel
multivariate genotype-phenotype mapping pipeline we developed to identify causal genes affecting OSA risk
through effects on craniofacial shape and/or tongue fat. In applying this method, this Aim leverages both existing
and newly generated data in a large sample of Diversity Outbred mice with genetic data and anatomical traits
quantified via imaging. This cutting-edge approach facilitates determination of the effects of multiple genes on
multivariate phenotypes using high-dimensional data to compare directions, not just magnitudes, of associations.
For sleepiness, Aim 3 will utilize Drosophila RNAi lines to study the impact of knocking-down candidate genes
on sleep-related phenotypes (including sleep amounts, sleep fragmentation, and sleep drive). Then, genes
shown to affect sleep in Drosophila will be validated in a vertebrate model by utilizing CRISPR-Cas9 methods to
knock-out these same genes in zebrafish and studying the effects on similar sleep phenotypes. Taken together,
results in this Project and the other projects in this Program will provide essential knowledge about effector genes
for OSA and for sleepiness in OSA in humans. This knowledge is crucial for understanding the biological and
clinical impact of GWAS associations, and will facilitate more efficient clinical translation and incorporation of
genetic evidence into precision medicine approaches to OSA, as well as provide an important resource for the
broader scientific community and proof of principle for the field of applied genomics in OSA.
摘要
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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Allan I Pack其他文献
A cGMP-dependent protein kinase plays a pivotal role in the control of behavioral quiescence in C. elegans
- DOI:
10.1186/1471-2210-5-s1-s8 - 发表时间:
2005-06-16 - 期刊:
- 影响因子:2.700
- 作者:
David M Raizen;Allan I Pack;Meera Sundaram - 通讯作者:
Meera Sundaram
Allan I Pack的其他文献
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{{ truncateString('Allan I Pack', 18)}}的其他基金
Developing a P4 Medicine Approach to Obstructive Sleep Apnea
开发治疗阻塞性睡眠呼吸暂停的 P4 医学方法
- 批准号:
10555805 - 财政年份:2023
- 资助金额:
$ 66.63万 - 项目类别:
Elucidating Genes Regulating Sleep Using Diversity Outbred Mice
利用多样性远交小鼠阐明调节睡眠的基因
- 批准号:
10623210 - 财政年份:2022
- 资助金额:
$ 66.63万 - 项目类别:
Elucidating Genes Regulating Sleep Using Diversity Outbred Mice
利用多样性远交小鼠阐明调节睡眠的基因
- 批准号:
10432369 - 财政年份:2022
- 资助金额:
$ 66.63万 - 项目类别:
Epigenetics: Opportunities for Sleep and Circadian Research
表观遗传学:睡眠和昼夜节律研究的机会
- 批准号:
8399335 - 财政年份:2012
- 资助金额:
$ 66.63万 - 项目类别:
Genetic Approaches to Sleep/Wake and Response to Sleep Loss in Mice
小鼠睡眠/觉醒的遗传方法以及对睡眠不足的反应
- 批准号:
8527842 - 财政年份:2012
- 资助金额:
$ 66.63万 - 项目类别:
Genetic Approaches to Sleep/Wake and Response to Sleep Loss in Mice
小鼠睡眠/觉醒的遗传方法以及对睡眠不足的反应
- 批准号:
8372470 - 财政年份:2012
- 资助金额:
$ 66.63万 - 项目类别:
Genetic Approaches to Sleep/Wake and Response to Sleep Loss in Mice
小鼠睡眠/觉醒的遗传方法以及对睡眠不足的反应
- 批准号:
8708190 - 财政年份:2012
- 资助金额:
$ 66.63万 - 项目类别:
Genetic Approaches to Sleep/Wake and Response to Sleep Loss in Mice
小鼠睡眠/觉醒的遗传方法以及对睡眠不足的反应
- 批准号:
8879193 - 财政年份:2012
- 资助金额:
$ 66.63万 - 项目类别:
Endophenotypes of Sleep Apnea and Role of Obesity
睡眠呼吸暂停的内表型和肥胖的作用
- 批准号:
8478277 - 财政年份:2009
- 资助金额:
$ 66.63万 - 项目类别:
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