Human population based genetic studies to elucidate the biology of NAFLD
基于人群的遗传学研究阐明 NAFLD 的生物学
基本信息
- 批准号:9009526
- 负责人:
- 金额:$ 77.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-10 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAlgorithmsBiological MarkersBiologyCandidate Disease GeneCell LineCell modelCellsCodeComplexComplex Genetic TraitDataDevelopmentDiagnosisDiseaseEtiologyEuropeanFatty LiverFrequenciesFunctional disorderGenderGene FrequencyGene TargetingGenesGeneticGenetic studyGenomeGenotypeGoalsHepaticHepatocyteHeritabilityHistologicHumanHuman Cell LineHuman GeneticsHypertriglyceridemiaIndividualInfluentialsLeadLinkage DisequilibriumLipidsLiverLiver diseasesMapsMeasuresMedicalMeta-AnalysisMetabolicMetabolic DiseasesMethodsMinorModelingPhenotypePopulationPreventionPropertyPublic HealthQuantitative Trait LociRNA SplicingResourcesSample SizeSamplingSignal TransductionSingle Nucleotide PolymorphismTestingTherapeuticTherapeutic InterventionTimeTriglyceridesUntranslated RNAVariantWorkX-Ray Computed Tomographyanalytical methodbasecohortexpression vectorfollow-upgenetic variantgenome wide association studygenome-wideimprovedknock-downloss of functionmeetingsnon-alcoholic fatty liveroverexpressionpopulation basedpreventpublic health relevancetargeted treatment
项目摘要
DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation), affects up to 29 million adults in the U.S. and will become
the leading cause of liver disease worldwide by 2020. There are few effective ways to prevent or treat NAFLD. A better understanding of NAFLD etiology is needed to improve its diagnosis and treatment. We previously determined that NAFLD is heritable (genetically influenced) and identified common (minor allele frequency (MAF) >5%) single nucleotide polymorphisms (SNPs) at 5 loci that associate with hepatic steatosis, first in ~7,000 individuals of European ancestry and then across ancestries. Variants at the 5 loci explain ~20% of heritability, suggesting the existence of more influential causal variants. We now aim to identify 1. causal genetic variants 2. gene(s) they work through to exert their effects, and 3. mechanism(s) by which they lead to disease. We tripled the sample size and ancestral diversity of our discovery sample, thus improving our ability to identify and fine-map causal variants. We will impute genome- wide genotypes to new denser and ancestrally diverse imputation panels, increasing our ability to identify causal common and now low-frequency (MAF 1-5%) variants across ancestries. We will use new analytical methods to perform not only single variant but also conditional and gene-based analyses across ancestries allowing us to efficiently identify causal single variants and genes. We will use new variant and gene annotations algorithms to prioritize variants and genes for functional follow up. Using this approach we identify new putative causal NAFLD variants and genes missed by previous analyses. Finally, we developed a human cell line model of NAFLD that we use to show that altering the function of three genes prioritized by the above approaches results in increased liver triglyceride accumulation, suggesting this as a common mechanism by which these genes cause NAFLD. We hypothesize that causal NAFLD-promoting human genetic variants have effects across ancestries and exert their effects in a cell-autonomous manner in hepatocytes to increase triglyceride accumulation. To test this hypothesis, we will harmonize the computed tomography hepatic steatosis phenotype and genotypes from 10 discovery cohorts (n>21K), impute genotypes to the 1000 Genomes cosmopolitan reference panel, and perform single variant, gene-based, and conditional meta- analyses across groups to identify, fine-map, and annotate putative causal variants and genes. We will follow- up top associating variants in >4,000 histologically confirmed NAFLD cases and ~3,000 controls to replicate our findings. We will knockdown and overexpress putative causal genes (wild-type and variant) in human liver cell lines and determine their effect on triglyceride accumulation and genetic mechanism of action. We will begin with three genes prioritized from our previous NAFLD meta-analysis and proceed to new genes identified from the 1000 Genomes meta-analysis. This work will help define the genetic and metabolic mechanisms that cause NAFLD and inform development of new biomarkers as well as potential therapeutics for this condition.
描述(由申请人提供):非酒精性脂肪肝 (NAFLD) 是由肝脏脂肪变性(脂质堆积)引起的,影响美国多达 2900 万成年人,并将成为
到 2020 年,NAFLD 将成为全球肝病的主要原因。目前几乎没有有效的方法来预防或治疗 NAFLD。需要更好地了解 NAFLD 病因以改进其诊断和治疗。我们之前确定 NAFLD 是可遗传的(受遗传影响),并在与肝脂肪变性相关的 5 个基因座上发现了常见的(次要等位基因频率 (MAF) > 5%)单核苷酸多态性 (SNP),首先是在约 7,000 名欧洲血统的个体中,然后是跨血统的个体。 5 个基因座的变异解释了约 20% 的遗传力,表明存在更具影响力的因果变异。我们现在的目标是确定 1. 因果遗传变异 2. 它们发挥作用的基因,以及 3. 它们导致疾病的机制。我们将发现样本的样本量和祖先多样性增加了两倍,从而提高了我们识别和精细绘制因果变异的能力。我们将把全基因组基因型归因于新的更密集和祖先多样化的归因小组,提高我们识别跨祖先因果常见变异和现在低频(MAF 1-5%)变异的能力。我们将使用新的分析方法不仅进行单一变异,而且还进行跨祖先的条件和基于基因的分析,使我们能够有效地识别因果单一变异和基因。我们将使用新的变异和基因注释算法来确定变异和基因的优先级,以进行功能跟踪。使用这种方法,我们确定了先前分析中遗漏的新的假定因果 NAFLD 变异和基因。最后,我们开发了 NAFLD 的人类细胞系模型,用于证明通过上述方法优先改变三个基因的功能会导致肝脏甘油三酯积累增加,表明这是这些基因导致 NAFLD 的常见机制。我们假设,导致 NAFLD 的人类遗传变异具有跨祖先的影响,并以细胞自主的方式在肝细胞中发挥作用,增加甘油三酯的积累。为了检验这一假设,我们将协调 10 个发现队列 (n>21K) 的计算机断层扫描肝脂肪变性表型和基因型,将基因型归入 1000 个基因组国际参考组,并跨组进行单变异、基于基因和条件荟萃分析,以识别、精细绘制和注释假定的因果变异和基因。我们将追踪超过 4,000 例经组织学证实的 NAFLD 病例和约 3,000 例对照中的顶级关联变异,以重复我们的研究结果。我们将在人类肝细胞系中敲低和过度表达假定的致病基因(野生型和变异型),并确定它们对甘油三酯积累的影响和遗传作用机制。我们将从之前的 NAFLD 荟萃分析中优先考虑的三个基因开始,然后继续研究从 1000 个基因组荟萃分析中确定的新基因。这项工作将有助于确定导致 NAFLD 的遗传和代谢机制,并为新生物标志物的开发以及这种疾病的潜在治疗方法提供信息。
项目成果
期刊论文数量(0)
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Elizabeth K Speliotes其他文献
Elizabeth K Speliotes的其他文献
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{{ truncateString('Elizabeth K Speliotes', 18)}}的其他基金
Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease
非酒精性脂肪肝的综合多基因遗传学研究
- 批准号:
10598159 - 财政年份:2022
- 资助金额:
$ 77.51万 - 项目类别:
Human population based genetic studies to elucidate the biology of NAFLD
基于人群的遗传学研究阐明 NAFLD 的生物学
- 批准号:
9549051 - 财政年份:2016
- 资助金额:
$ 77.51万 - 项目类别:
Human population based genetic studies to elucidate the biology of NAFLD
基于人群的遗传学研究阐明 NAFLD 的生物学
- 批准号:
10020952 - 财政年份:2016
- 资助金额:
$ 77.51万 - 项目类别:
Human population based genetic studies to elucidate the biology of NAFLD
基于人群的遗传学研究阐明 NAFLD 的生物学
- 批准号:
9348637 - 财政年份:2016
- 资助金额:
$ 77.51万 - 项目类别:
Identification and functional impact of NAFLD associated genetic variants
NAFLD 相关基因变异的鉴定和功能影响
- 批准号:
9506752 - 财政年份:2015
- 资助金额:
$ 77.51万 - 项目类别:
Identification and functional impact of NAFLD associated genetic variants
NAFLD 相关基因变异的鉴定和功能影响
- 批准号:
8945536 - 财政年份:2015
- 资助金额:
$ 77.51万 - 项目类别:
Analysis of Fatty Liver in the Framingham Heart Study Cohort
弗雷明汉心脏研究队列中的脂肪肝分析
- 批准号:
7361956 - 财政年份:2008
- 资助金额:
$ 77.51万 - 项目类别:
Analysis of Fatty Liver in the Framingham Heart Study Cohort
弗雷明汉心脏研究队列中的脂肪肝分析
- 批准号:
8018094 - 财政年份:2008
- 资助金额:
$ 77.51万 - 项目类别:
Analysis of Fatty Liver in the Framingham Heart Study Cohort
弗雷明汉心脏研究队列中的脂肪肝分析
- 批准号:
7570647 - 财政年份:2008
- 资助金额:
$ 77.51万 - 项目类别:
Analysis of Fatty Liver in the Framingham Heart Study Cohort
弗雷明汉心脏研究队列中的脂肪肝分析
- 批准号:
7784451 - 财政年份:2008
- 资助金额:
$ 77.51万 - 项目类别:
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