Population genetics for large-scale sequencing studies of diverse populations
用于不同人群大规模测序研究的群体遗传学
基本信息
- 批准号:10518819
- 负责人:
- 金额:$ 55.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-13 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AchievementAddressAdmixtureAffectAlgorithmsAllelesChromosome abnormalityCollaborationsCollectionComplexComputer softwareCopy Number PolymorphismDataData SetDemographyDetectionDiseaseEuropeanEvolutionExplosionFrequenciesFundingGene FrequencyGenealogyGenesGeneticGenetic DiseasesGenetic ModelsGenetic PhenomenaGenetic ProcessesGenetic StructuresGenetic VariationGenomeGenomicsGenotypeGrowthHaplotypesHomozygoteHumanHuman GeneticsInbreedingIndividualInheritedInvestigationLarge-Scale SequencingLengthLightLinkLinkage DisequilibriumLoss of HeterozygosityMeasuresMedicalMendelian disorderMethodsMichiganModelingMosaicismNatural SelectionsPartner in relationshipPatternPhasePhenotypePlayPopulationPopulation DistributionsPopulation GeneticsPopulation HeterogeneityPopulation SizesPopulation StudyQuality ControlRare DiseasesRecording of previous eventsReportingResearch DesignResearch PersonnelRiskRoleRunningSamplingSignal TransductionStatistical Data InterpretationStructureTechniquesTestingTheoretical modelUnderrepresented PopulationsVariantbiobankcancer riskcase controlcohortdesigndisorder riskgene environment interactiongene interactiongenetic architecturegenetic variantgenome sequencinggenome wide association studygenome-widegenomic datahuman diseasehuman population geneticshuman population studyinsightlarge datasetsnovel strategiesphenomepopulation basedpreferenceprogramsrare variantrecessive genetic traitrisk variantsuccesstooltraituser friendly softwarewhole genome
项目摘要
Summary
Population-based studies identifying the genetic variants that affect complex human diseases have relied
heavily on population-genetic principles in important tasks such as study design, quality control, and genotype
imputation. The dramatic growth of large-scale genotyping and sequencing studies of disease generates new
challenges both for modeling the underlying generative population-genetic processes that give rise to evidence
of disease association in data sets and for performing statistical analysis to uncover disease variants. These
challenges magnify the potential for approaches grounded in population genetics to maximize the return from
ongoing investigations. Because studies thus far have often focused on populations of European descent, it is
critical that new methods provide tools for a greater diversity of populations. This project builds on productive
efforts in two previous funding periods, capitalizing on the study of human population genetics to enhance the
design, analysis, and interpretation of genomic studies of disease. It exploits the fundamental principle of
human genetics that population-genetic phenomena are responsible for homozygous placement of recessive
risk variants, and the recent recognition that accumulations of runs of homozygosity (ROH), and hence, of
multiple recessive deleterious variants of small effect in homozygous form, can contribute to disease risk.
Particularly for large-scale genotyping and low-coverage sequencing studies, in which rare recessive variants
are difficult to analyze, this project uses the population genetics of ROH to enhance discovery. The project
expands beyond the setting of rare diseases in small populations, building on observations that ROH and
accumulations of recessive deleterious variants of small effect contribute to complex disease risk in outbred
groups, including admixed populations. (1) We will construct models of the effects of interacting population-
genetic forces on ROH. Such models will make it possible for researchers to attribute ROH patterns to effects
of inbreeding, population size history, admixture, and selection against deleterious recessive variants. (2) We
will develop powerful new tests that measure effects of ROH on complex disease risk. These tests will employ
population-genetic models that incorporate features of genetic architecture and genomic parameters to assess
if associations between ROH and disease reflect the likely presence of recessive disease variants. (3) We will
differentiate between germline and somatically acquired homozygosity, leveraging signals in intermediate data
types and genotype distributions from population genetics, to identify false-positive ROH and to refine
detection of chromosomal alterations. (4) We will comprehensively evaluate the impact of ROH on medical
traits in multiple disease studies, using the Michigan Genomics Initiative and UK Biobank to test and inform our
approaches. The application of association testing between ROH and disease will contribute a phenome-wide
association study to identify traits for which ROH variables possess meaningful predictive connections to
phenotypes. To facilitate use of our methods, we will produce, test, and distribute new user-friendly software.
摘要
基于人群的研究确定了影响复杂人类疾病的遗传变异,这依赖于
在研究设计、质量控制和基因分型等重要任务中高度依赖群体遗传学原理
推卸责任。大规模疾病基因分型和测序研究的戏剧性增长产生了新的
对潜在的生殖种群--产生证据的遗传过程进行建模的挑战
对数据集中的疾病关联进行分析,并执行统计分析以发现疾病变体。这些
挑战放大了以群体遗传学为基础的方法的潜力,以最大化从
正在进行的调查。因为到目前为止,研究往往集中在欧洲血统的人群上,所以
至关重要的是,新的方法为更多样化的人口提供了工具。这个项目建立在多产的基础上
前两个资助期的努力,利用对人类种群遗传学的研究,加强
疾病基因组研究的设计、分析和解释。它利用了以下基本原理
人类遗传学认为群体遗传现象是隐性基因纯合子放置的原因
风险变异,以及最近认识到纯合子(ROH)的累积,因此,
在纯合子形式中影响小的多个隐性有害变异,可增加疾病风险。
尤其是对于大规模的基因分型和低覆盖率的测序研究,在这些研究中,罕见的隐性变异
很难分析,这个项目使用了ROH的群体遗传学来加强发现。该项目
扩展到小人口中罕见疾病的背景之外,建立在观察到的ROH和
小效应隐性有害变异的积累对近交种的复杂疾病风险有贡献
群体,包括混杂种群。(1)我们将构建人口相互作用的影响模型-
ROH上的遗传力。这样的模型将使研究人员有可能将ROH模式归因于效应
近亲交配、种群规模历史、混合和针对有害隐性变异的选择。(2)我们
将开发强大的新测试,以衡量ROH对复杂疾病风险的影响。这些测试将使用
结合遗传结构特征和基因组参数的种群遗传模型
如果ROH和疾病之间的关联反映了隐性疾病变异的可能存在。(3)我们会
利用中间数据中的信号,区分生殖系和体细胞获得的纯合性
从群体遗传学角度识别假阳性ROH的类型和基因分布
染色体改变的检测。(四)全面评估ROH对医疗卫生的影响
在多种疾病研究中的特征,使用密歇根基因组学倡议和英国生物库来测试和告知我们的
接近了。ROH与疾病的关联性检验的应用将有助于在全社会范围内
识别ROH变量对其具有有意义的预测联系的性状的关联研究
表型。为了方便使用我们的方法,我们将生产、测试和分发新的用户友好型软件。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Noah Rosenberg其他文献
Noah Rosenberg的其他文献
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{{ truncateString('Noah Rosenberg', 18)}}的其他基金
Population genetics for large-scale sequencing studies of diverse populations
用于不同人群大规模测序研究的群体遗传学
- 批准号:
10709562 - 财政年份:2010
- 资助金额:
$ 55.89万 - 项目类别:
Population genetics for large-scale sequencing studies of diverse populations
用于不同人群大规模测序研究的群体遗传学
- 批准号:
10063406 - 财政年份:2010
- 资助金额:
$ 55.89万 - 项目类别:
Population-Genetic Studies for Association Mapping
关联作图的群体遗传学研究
- 批准号:
7901901 - 财政年份:2009
- 资助金额:
$ 55.89万 - 项目类别:
Population-Genetic Studies for Association Mapping
关联作图的群体遗传学研究
- 批准号:
8055339 - 财政年份:2007
- 资助金额:
$ 55.89万 - 项目类别:
Population-Genetic Studies for Association Mapping
关联作图的群体遗传学研究
- 批准号:
7248301 - 财政年份:2007
- 资助金额:
$ 55.89万 - 项目类别:
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