Genome-wide fine-mapping of metabolic traits in heterogeneous stock rats
异种大鼠代谢特征的全基因组精细图谱
基本信息
- 批准号:8586063
- 负责人:
- 金额:$ 0.15万
- 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:2010-08-01 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAffectAllelesAnimal ModelAnimalsAreaBlindnessBody WeightBody fatBreedingCandidate Disease GeneCholesterolChromosome MappingChromosomesComplexConfidence IntervalsDiabetes MellitusDiseaseExhibitsFastingGenesGeneticGenetic RecombinationGenomeGenotypeGlucoseGoalsGrantHeart DiseasesHumanHuman GenomeInbred StrainInbreedingInsulinKidney FailureLaboratoriesMapsMeasurementMeasuresMentored Research Scientist Development AwardMetabolicMetabolic DiseasesMethodsNon-Insulin-Dependent Diabetes MellitusPatternPeptidesPhenotypePlasmaPlayPopulationPrevalencePreventionQuantitative Trait LociRattusRecombinantsResolutionResourcesRisk FactorsRoleSequence AnalysisSingle Nucleotide PolymorphismStrokeStructureTechnologyTestingTissuesTriglyceridesVariantWeightWorkblood glucose regulationdesignfamily structurefasting glucosefollow-upgene discoverygenetic resourcegenome wide association studygenome-wideglucose toleranceimprovedlimb amputationmRNA Expressionnovelpositional cloningpublic health relevanceresponsetrait
项目摘要
DESCRIPTION (provided by applicant):
Project Summary: Type 2 diabetes (T2D) affects more than 170 million people worldwide and this number is expected to double by 2025 (91). T2D is a leading cause of kidney failure, blindness and limb amputation and a major risk factor for heart disease and stroke (18). Understanding the genetic mechanisms involved in T2D will help in prevention and treatment of this disease. While many genes have recently been identified in human genome wide association studies (GWAS), these genes explain only a small percentage of the population variance (94), indicating that many more genes have yet to be identified. My laboratory has successfully used a unique genetic resource, heterogeneous stock (HS) rats, to fine- map multiple metabolic traits within a single region on rat chromosome one. The confidence interval of many of these loci was less than 5 Megabases. This resource leverages existing recombinations (the major limitation in positional cloning) in the animals, markedly improving map resolution. We are now poised to accelerate the discovery of loci genome-wide using HS rats. We hypothesize that this resource will be useful for rapidly fine-mapping metabolic traits genome-wide, thereby providing a resource to identify novel genes involved in T2D and other metabolic disorders. To date, our laboratory has phenotyped over 500 HS rats for multiple metabolic phenotypes (glucose and insulin after a glucose challenge, fasting plasma cholesterol and triglyceride levels, body weight and fat pad weight). In Specific Aim 1 of this proposal, we will fine-map these traits genome-wide using HS rats. We plan to phenotype an additional 500 rats and genotype these 1000 animals using the Affymetrix 10K single nucleotide polymorphism array. We will identify fine-mapped loci using single and multiple locus mapping methods. We expect to identify 3-15 loci across the genome for each trait measured and will follow-up at least one of these new loci in the following aim. In Specific Aim 2 of this proposal, we plan to identify a gene or genes involved in diabetes or metabolic disorders within one of the fine-mapped regions identified in Specific Aim 1. We will use both sequencing and expression analyses to narrow candidate genes within this region. Importantly, the multiple alleles found in the HS provide increased power for identifying candidate variants. The goal of the sequencing analysis will be to narrow the candidate variants within this region from several thousand to less than 100. These variants will then serve as a means for prioritizing candidate genes to be tested further using mRNA expression analysis in metabolically relevant tissues. The major impact of this work will be to accelerate discovery of genes involved in T2D and related metabolic disorders to a level that has not previously been possible using conventional mapping methods in animal models.
描述(由申请人提供):
项目摘要:2 型糖尿病 (T2D) 影响着全球超过 1.7 亿人,预计到 2025 年这一数字将增加一倍 (91)。 T2D 是肾衰竭、失明和截肢的主要原因,也是心脏病和中风的主要危险因素 (18)。了解 T2D 的遗传机制将有助于预防和治疗该疾病。虽然最近在人类全基因组关联研究 (GWAS) 中鉴定出了许多基因,但这些基因仅解释了群体方差的一小部分 (94),这表明还有更多基因有待鉴定。我的实验室成功地使用了一种独特的遗传资源,即异质种(HS)大鼠,精细绘制了大鼠一号染色体上单个区域内的多种代谢特征。其中许多位点的置信区间小于 5 兆碱基。该资源利用了动物中现有的重组(定位克隆的主要限制),显着提高了图谱分辨率。我们现在准备利用 HS 大鼠加速全基因组基因座的发现。我们假设该资源将有助于快速精细绘制全基因组代谢特征,从而提供识别与 T2D 和其他代谢紊乱相关的新基因的资源。迄今为止,我们的实验室已对 500 多只 HS 大鼠进行了多种代谢表型(葡萄糖激发后的血糖和胰岛素、空腹血浆胆固醇和甘油三酯水平、体重和脂肪垫重量)的表型分析。在本提案的具体目标 1 中,我们将使用 HS 大鼠在全基因组范围内精细绘制这些特征。我们计划对另外 500 只大鼠进行表型分析,并使用 Affymetrix 10K 单核苷酸多态性阵列对这 1000 只动物进行基因分型。我们将使用单基因座定位方法和多基因座定位方法来识别精细定位的基因座。我们期望为每个测量的性状在基因组中识别 3-15 个基因座,并将在以下目标中跟踪至少其中一个新基因座。在该提案的具体目标 2 中,我们计划在具体目标 1 中确定的精细映射区域之一内鉴定与糖尿病或代谢紊乱有关的一个或多个基因。我们将使用测序和表达分析来缩小该范围内的候选基因范围。地区。重要的是,HS 中发现的多个等位基因为识别候选变体提供了更强的能力。测序分析的目标是将这个区域内的候选变体从数千个缩小到不到100个。然后,这些变体将作为优先考虑候选基因的手段,以便在代谢相关组织中使用mRNA表达分析进一步测试。这项工作的主要影响将是加速发现与 T2D 和相关代谢紊乱相关的基因,达到以前在动物模型中使用传统作图方法无法达到的水平。
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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Leah Catherine Solberg Woods其他文献
Leah Catherine Solberg Woods的其他文献
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{{ truncateString('Leah Catherine Solberg Woods', 18)}}的其他基金
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
10443753 - 财政年份:2019
- 资助金额:
$ 0.15万 - 项目类别:
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
9914686 - 财政年份:2019
- 资助金额:
$ 0.15万 - 项目类别:
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
10646341 - 财政年份:2019
- 资助金额:
$ 0.15万 - 项目类别:
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
10194486 - 财政年份:2019
- 资助金额:
$ 0.15万 - 项目类别:
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
10020972 - 财政年份:2019
- 资助金额:
$ 0.15万 - 项目类别:
Systems Genetics of Adiposity Traits in Outbred Rats
远交大鼠肥胖性状的系统遗传学
- 批准号:
9421356 - 财政年份:2015
- 资助金额:
$ 0.15万 - 项目类别:
Systems Genetics of Adiposity Traits in Outbred Rats
远交大鼠肥胖性状的系统遗传学
- 批准号:
9145731 - 财政年份:2015
- 资助金额:
$ 0.15万 - 项目类别:
Center for Genetic Studies of Drug Abuse in Outbred Rats
近交系大鼠药物滥用基因研究中心
- 批准号:
10160844 - 财政年份:2014
- 资助金额:
$ 0.15万 - 项目类别:
Center for Genetic Studies of Drug Abuse in Outbred Rats
近交系大鼠药物滥用基因研究中心
- 批准号:
10402307 - 财政年份:2014
- 资助金额:
$ 0.15万 - 项目类别:
Center for Genetic Studies of Drug Abuse in Outbred Rats
近交系大鼠药物滥用基因研究中心
- 批准号:
10613525 - 财政年份:2014
- 资助金额:
$ 0.15万 - 项目类别:
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