Identification and characterization of inflammatory bowel disease causal variants
炎症性肠病致病变异的鉴定和表征
基本信息
- 批准号:10679091
- 负责人:
- 金额:$ 69.18万
- 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:2022-08-15 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdolescenceAffectAfricanAlgorithmsAmericanAutoimmune DiseasesBinding SitesBiologicalBiologyCRISPR interferenceCRISPR-mediated transcriptional activationCellsChromosome MappingChronicChronic DiseaseCodeDataData SetDigestive System DisordersEast AsianEnsureEuropeanEuropean ancestryGene Expression RegulationGene FrequencyGene TargetingGeneticGenetic DiseasesGenetic studyGenomeGenomic SegmentGenomicsGenotypeGoalsHealth Care CostsHeritabilityHeterogeneityHistonesHumanHuman GeneticsIndividualInflammatory Bowel DiseasesInternationalKnock-inKnowledgeLinkLinkage DisequilibriumMapsMeta-AnalysisMethodologyMethodsMolecularNatureOutcomePathogenesisPathway interactionsPersonsPopulationPrintingProbabilityProcessQuality ControlResolutionResourcesRestSample SizeSamplingSeriesSiteT-LymphocyteTechnologyTestingTherapeuticTissuesUncertaintyUnited States National Institutes of HealthUntranslated RNAVariantcausal variantcohortdata harmonizationdesigndisorder riskemerging adultexome sequencingexperimental studygenetic associationgenetic technologygenetic variantgenome resourcegenome wide association studygenomic datagenomic locusgenotyping technologyhealth disparityimprovedin silicoinsightnovelpleiotropismprotein functionsuccesstranscription factorweb portal
项目摘要
PROJECT SUMMARY/ABSTRACT
Inflammatory bowel diseases (IBD) are a group of chronic, debilitating disorders of the gastrointestinal tract with
peak onset in adolescence and early adulthood. More than 3 million people are affected in U.S., with an
estimated direct healthcare cost of $6.3 billion per year. IBD are highly heritable, thus, studying the genetic basis
of IBD is a natural path towards elucidating the IBD pathogenesis, which is poorly understood at present.
Genome-wide association studies have identified over 240 loci associated with IBD. These associations
typically implicate large genomic regions with hundreds of variants due to the linkage disequilibrium (LD). The
latest IBD fine-mapping study resolved the LD and mapped 45 IBD associations to single-variant resolution,
providing insights into how genetic variants contribute to IBD pathogenesis in a tissue specific manner. Despite
of this initial success, most IBD associations and putative causal variants to date were derived from European
ancestries with uncertainty in their transferability to non-European ancestries; and the functional impact for most
IBD causal variants, especially the noncoding variants, is unclear.
This proposed study bridges these gaps through an integrative strategy combining fine-mapping on a
large-scale multi-ancestry IBD cohort and well-designed functional experiments to investigate the genetic basis
of IBD. This cohort includes subjects of four ancestral populations including African, admixed American, East
Asian and European, with an unprecedented sample size of over 192,600 IBD cases, 3x, 12x, 5x and 3x of the
current IBD sample size for each ancestry respectively. A large amount of exome sequencing (WES) data will
be included, allowing us to investigate the contribution from rare coding variants which have been shown to be
important to IBD and help to link noncoding variants to their gene targets. Extensive quality control and
harmonization will be performed to generate a high quality, high coverage individual-level dataset with minimal
heterogeneity across ancestries, technologies, and batches. A novel fine-mapping method will be developed to
leverage the genomic diversity across ancestries and the WES data with the goal to enhance the fine-mapping
resolution especially in the coding genome. Over 200 new IBD causal variants are expected from this study,
including many that have large effects and directly disrupt protein functions. These variants will be characterized
for their molecular and cellular mechanism in IBD in human T cells using pooled CRISPR activation and CRISPR
interference experiments, and knockins of coding variants for their effects on gene regulation in resting and
stimulated cells.
The new IBD causal variants and biology from this study will provide new insights into IBD pathogenesis,
make important positive impact and serve as the fundamental resource and basis toward novel IBD therapeutics.
项目总结/摘要
炎症性肠病(IBD)是一组慢性、使人衰弱的胃肠道疾病,
青春期和成年早期发病高峰。美国有300多万人受到影响,与
估计每年直接医疗费用为63亿美元。IBD具有高度遗传性,因此,研究遗传基础
对IBD的研究是阐明IBD发病机制的自然途径,目前对其了解甚少。
全基因组关联研究已经确定了超过240个与IBD相关的基因座。这些协会
由于连锁不平衡(LD),通常涉及具有数百个变体的大基因组区域。的
最新的IBD精细定位研究解决了LD,并将45个IBD关联映射到单变量分辨率,
提供了对遗传变异如何以组织特异性方式促进IBD发病机制的见解。尽管
在这一初步成功中,迄今为止,大多数IBD关联和推定的因果变异来自欧洲人,
祖先与非欧洲祖先的可转移性的不确定性;以及对大多数人的功能影响
IBD致病变异,特别是非编码变异,尚不清楚。
这项拟议的研究通过一项综合战略,将精细映射与
大规模多祖先IBD队列和精心设计的功能实验,以研究遗传基础
IBD。该队列包括四个祖先群体的受试者,包括非洲人、混血美国人、东
亚洲和欧洲,前所未有的样本量超过192,600例IBD病例,分别为3x、12 x、5x和3x。
每个祖先的当前IBD样本量。大量的外显子组测序(WES)数据将
包括在内,使我们能够调查罕见的编码变异的贡献,这些变异已被证明是
这对IBD很重要,并有助于将非编码变体与其基因靶点联系起来。广泛的质量控制和
将进行协调,以生成高质量、高覆盖率的个人层面数据集,只需最少的
跨祖先、技术和批次的异质性。将开发一种新的精细映射方法,
利用祖先之间的基因组多样性和WES数据,以增强精细定位
特别是在编码基因组中。本研究预计将产生超过200种新的IBD致病变异,
包括许多具有大作用并直接破坏蛋白质功能的药物。这些变体将被表征为
使用合并的CRISPR活化和CRISPR抑制,在人T细胞中的IBD中的分子和细胞机制
干扰实验,以及编码变体的敲入,以了解其对静息和
刺激细胞
来自这项研究的新的IBD致病变体和生物学将为IBD发病机制提供新的见解,
产生了重要的积极影响,并成为IBD新疗法的基本资源和基础。
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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Hailiang Huang其他文献
Hailiang Huang的其他文献
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{{ truncateString('Hailiang Huang', 18)}}的其他基金
1/4 Asian Bipolar Genetics Network (A-BIG-NET)
1/4 亚洲双相遗传学网络(A-BIG-NET)
- 批准号:
10501841 - 财政年份:2022
- 资助金额:
$ 69.18万 - 项目类别:
Identification and characterization of inflammatory bowel disease causal variants
炎症性肠病致病变异的鉴定和表征
- 批准号:
10442851 - 财政年份:2022
- 资助金额:
$ 69.18万 - 项目类别:
1/4 Asian Bipolar Genetics Network (A-BIG-NET)
1/4 亚洲双相遗传学网络(A-BIG-NET)
- 批准号:
10706617 - 财政年份:2022
- 资助金额:
$ 69.18万 - 项目类别:
Genetics and gene regulation in the inflammatory bowel diseases
炎症性肠病的遗传学和基因调控
- 批准号:
9564893 - 财政年份:2017
- 资助金额:
$ 69.18万 - 项目类别:
Genetics and gene regulation in the inflammatory bowel diseases
炎症性肠病的遗传学和基因调控
- 批准号:
9751298 - 财政年份:2017
- 资助金额:
$ 69.18万 - 项目类别:
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