Characterizing the evolutionary architecture of complex disease within and across diverse populations
表征不同人群内部和不同人群之间复杂疾病的进化结构
基本信息
- 批准号:10653221
- 负责人:
- 金额:$ 71.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAllelesArchitectureAtlasesAwarenessBiological AssayCatalogsCellsComplexCoupledDataDiseaseEthnic OriginEtiologyEuropean ancestryExhibitsFrequenciesGene FrequencyGenesGeneticGenetic ModelsGenetic RiskGenetsGenomeGenomicsGeographyHeritabilityHeterogeneityIndividualInheritedLinkage DisequilibriumMapsMediatingMessenger RNAMethodsModelingMolecularNatural SelectionsPathway interactionsPerformancePeripheralPhenotypePopulationPopulation HeterogeneityProceduresReduce health disparitiesReporterReproducibilityResearch PersonnelResolutionRiskRoleRunningSample SizeShapesSignal TransductionSusceptibility GeneTestingTranslatingWorkcausal variantdirect applicationdisease phenotypedisorder riskdisparity reductionexperimental studyfunctional genomicsgenetic architecturegenetic variantgenome wide association studygenome-widehealth disparityimprovedlarge scale datamenmetabolic abnormality assessmentmolecular modelingmolecular phenotypemolecular scalemolecular shapemulti-ethnicnovelnovel strategiesopen sourcepolygenic risk scorepopulation stratificationpressurerisk predictionstatisticstraittranscriptomics
项目摘要
PROJECT SUMMARY
The past decade of genome-wide association studies (GWASs) has seen thousands of complex traits and
diseases studied and identified thousands of reproducibly associated genetic variants. GWAS has helped
characterize the complexity of common genetic architectures and shed light on the role of genetics in disease
risk. A large body of works have demonstrated that risks of complex traits are highly enriched in functional regions
of the genome, which indicates that risk is mediated through perturbed regulatory action on relevant susceptibility
genes. Similarly, multiple recent works have found that disease risks are shaped by forces of natural selection,
which kept the frequencies of deleterious alleles low in the population. Together, the functional mechanisms and
their interplay with natural selection can be coupled under a general mechanism we refer to as the evolutionary
architecture. Current frameworks to infer the evolutionary architecture for common complex diseases are only
applicable to relatively homogenous populations, such as individuals of European ancestry. Several recent works
have demonstrated that integrating multi-ethnic GWAS data substantially improves statistical power to identify
causal factors underlying complex traits and diseases due to the increased heterogeneity in allele frequencies.
Current approaches evolutionary architecture are unable to appropriately model the heterogeneity across
populations with respect to allele frequencies and linkage disequilibrium. Similarly, the resolution of these
methods is currently limited to complex diseases and phenotypes, whose inferred architectures, while
informative, fail to describe regulatory network mechanisms that mediate risk. Methods capable of analyzing
many molecular phenotypes simultaneously have the potential to identify shared architectures, and pinpoint core
genes relevant for disease risk. Lastly, several works have shown that integrating functional information with
GWAS substantially improves polygenic risk prediction. Together, these issues and opportunities highlight the
need for new computational approaches that can scale to multiple populations and large-scale molecular
phenotype catalogues while accounting for underlying heterogeneity and shared signals. Here, we propose novel
approaches to integrate GWAS data from multiple, geographically diverse, populations and phenotypes to
characterize the population-specific and shared evolutionary architectures. Importantly, our approaches run
directly on summary data, which enables immediate large-scale analysis. We propose to apply our novel
approaches to large-scale multi-ethnic GWAS data. Together, our work will systematically characterize
evolutionary architectures for complex diseases and molecular phenotypes and populations in a robust, open,
and reproducible approach.
项目摘要
全基因组关联研究(GWASS)的过去十年已经看到了成千上万的复杂特征和
疾病研究并确定了数千种可重复相关的遗传变异。 GWAS提供了帮助
表征常见遗传结构的复杂性,并阐明了遗传学在疾病中的作用
风险。大量作品表明,复杂性状的风险在功能区域高度丰富
基因组,这表明风险是通过对相关易感性的扰动调节作用介导的
基因。同样,最近的多项作品发现,疾病风险是由自然选择的力量塑造的,
这使人口中有害等位基因的频率保持较低。在一起,功能机制和
它们与自然选择的相互作用可以在我们称为进化的一般机制下耦合
建筑学。当前推断常见复杂疾病进化架构的框架仅是
适用于相对同质的人群,例如欧洲血统的个人。最近的一些作品
已经证明,整合多种族GWAS数据可大大提高统计能力以识别
由于等位基因频率的异质性增加而引起的复杂性状和疾病的原因。
当前的进化架构无法适当建模跨越的异质性
人口相对于等位基因频率和连锁不平衡。同样,这些解决方案
方法目前仅限于复杂的疾病和表型,它们的推断结构,而
信息性,无法描述介导风险的监管网络机制。能够分析的方法
许多分子表型同时具有识别共享体系结构的潜力,并确定了核心
与疾病风险相关的基因。最后,几项作品表明,将功能信息与
GWAS大大改善了多基因风险预测。这些问题和机遇共同强调了
需要新的计算方法,可以扩展到多个人群和大规模分子
表型目录在考虑基本异质性和共享信号的同时。在这里,我们提出小说
将来自多个,地理上不同,人群和表型的GWA数据整合到的方法
表征人口特定和共享的进化体系结构。重要的是,我们的方法运行
直接基于摘要数据,可以立即进行大规模分析。我们建议应用我们的小说
大规模多种族GWAS数据的方法。在一起,我们的工作将系统地描述
在强大,开放的情况下,用于复杂疾病和分子表型和种群的进化体系结构
和可再现的方法。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Estimating heritability explained by local ancestry and evaluating stratification bias in admixture mapping from summary statistics.
估计由当地血统解释的遗传力,并根据汇总统计评估混合映射中的分层偏差。
- DOI:10.1101/2023.04.10.536252
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Chan,TszFung;Rui,Xinyue;Conti,DavidV;Fornage,Myriam;Graff,Mariaelisa;Haessler,Jeffrey;Haiman,Christopher;Highland,HeatherM;Jung,SuYon;Kenny,Eimear;Kooperberg,Charles;Marchland,LoicLe;North,KariE;Tao,Ran;Wojcik,Genevieve;
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nicholas Mancuso其他文献
Nicholas Mancuso的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nicholas Mancuso', 18)}}的其他基金
An integrative multi-omics approach to characterize prostate cancer risk in diverse populations
一种综合多组学方法来表征不同人群中前列腺癌的风险
- 批准号:
10452535 - 财政年份:2021
- 资助金额:
$ 71.92万 - 项目类别:
Characterizing the evolutionary architecture of complex disease within and across diverse populations
表征不同人群内部和不同人群之间复杂疾病的进化结构
- 批准号:
10302919 - 财政年份:2021
- 资助金额:
$ 71.92万 - 项目类别:
An integrative multi-omics approach to characterize prostate cancer risk in diverse populations
一种综合多组学方法来表征不同人群中前列腺癌的风险
- 批准号:
10186390 - 财政年份:2021
- 资助金额:
$ 71.92万 - 项目类别:
An integrative multi-omics approach to characterize prostate cancer risk in diverse populations
一种综合多组学方法来表征不同人群中前列腺癌的风险
- 批准号:
10657510 - 财政年份:2021
- 资助金额:
$ 71.92万 - 项目类别:
相似国自然基金
等位基因聚合网络模型的构建及其在叶片茸毛发育中的应用
- 批准号:32370714
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
基于等位基因非平衡表达的鹅掌楸属生长量杂种优势机理研究
- 批准号:32371910
- 批准年份:2023
- 资助金额:50.00 万元
- 项目类别:面上项目
基于人诱导多能干细胞技术研究突变等位基因特异性敲除治疗1型和2型长QT综合征
- 批准号:82300353
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
ACR11A不同等位基因调控番茄低温胁迫的机理解析
- 批准号:32302535
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
肠杆菌多粘菌素异质性耐药中phoPQ等位基因差异介导不同亚群共存的机制研究
- 批准号:82302575
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
p16INK4a+ fibroblasts regulate epithelial regeneration after injury in lung alveoli through the SASP
p16INK4a成纤维细胞通过SASP调节肺泡损伤后的上皮再生
- 批准号:
10643269 - 财政年份:2023
- 资助金额:
$ 71.92万 - 项目类别:
Molecular analysis of glutamatergic neurons derived from iPSCs containing PPM1D truncating mutations found in Jansen de Vries Syndrome
Jansen de Vries 综合征中发现的含有 PPM1D 截短突变的 iPSC 衍生的谷氨酸能神经元的分子分析
- 批准号:
10573782 - 财政年份:2023
- 资助金额:
$ 71.92万 - 项目类别:
Genetic regulation of genes on active and inactive X chromosome and their contribution to sex-biased diseases
活性和非活性 X 染色体上基因的遗传调控及其对性别偏见疾病的贡献
- 批准号:
10751331 - 财政年份:2023
- 资助金额:
$ 71.92万 - 项目类别:
Mechanisms linking the frail sarcomere to noncompaction cardiomyopathy
脆弱肌节与非致密化心肌病的相关机制
- 批准号:
10643016 - 财政年份:2023
- 资助金额:
$ 71.92万 - 项目类别:
Assembly and re-alignment of HLA genomic region and its implication for fine-mapping suicidality in African descent population
HLA基因组区域的组装和重新排列及其对非洲人后裔自杀倾向精细定位的意义
- 批准号:
10797122 - 财政年份:2023
- 资助金额:
$ 71.92万 - 项目类别: