Allele Specific and Parent of Origin Effects on Gene Expression and Cardiovascular Disease Associated Traits
等位基因特异性和亲本对基因表达和心血管疾病相关性状的影响
基本信息
- 批准号:9192024
- 负责人:
- 金额:$ 4.36万
- 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:2016-09-30 至 2018-12-29
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAffectAllelesAllelic ImbalanceArchitectureBlood PressureCanadaCardiovascular DiseasesCarotid ArteriesCause of DeathCell CountCholesterolChromosomesComplexDataDiploidyDiseaseEuropeanEvolutionFathersFounder GenerationGene ExpressionGene Expression RegulationGene FrequencyGenerationsGenesGeneticGenetic PolymorphismGenetic Predisposition to DiseaseGenetic VariationGenetic studyGenotypeGoalsHaplotypesHeart AtriumHeritabilityHigh Density LipoproteinsHigh-Throughput RNA SequencingHumanIndividualInflammatoryInheritedKnowledgeLeftLeft Ventricular MassLifeLightLipidsLipoprotein (a)Low-Density LipoproteinsMapsMeasurementMeasuresMethodsMinorModelingMolecular Mechanisms of ActionMothersNucleic Acid Regulatory SequencesParentsPathogenesisPhenotypePlayPopulationPredispositionQuantitative Trait LociReadingResourcesRoleSamplingSiteSusceptibility GeneTestingThickTranscriptTriglyceridesVariantWhole BloodWomanbasecardiovascular disorder riskdisease phenotypedisease-causing mutationgenetic pedigreegenome sequencinggenome wide association studygenome-widehutteriteimprintinsightinterestlymphoblastoid cell linemennorthern plainsnovelnovel strategiesprogramsrisk varianttraittranscriptometranscriptome sequencingwhole genome
项目摘要
PROJECT ABSTRACT:
The overall goal of this project is to evaluate novel strategies for identifying genetic variation that contributes to
common, complex diseases, with a specific focus on variants that contribute to cardiovascular disease (CVD)
risk through parent of origin effects. CVD is the leading cause of death among men and women, and while
genome wide association studies (GWAS) have identified some genetic loci that contribute to CVD risk, a lot
still remains unknown. The risk alleles identified by GWAS explain little of the heritability of the trait and some
of this “missing heritability” has been attributed to parent of origin effects. I propose to bridge this gap of
knowledge by characterizing parent of origin effects on gene expression and on CVD associated phenotypes
and calculate parent of origin heritability for CVD phenotypes in the Hutterites. The Hutterites are a founder
population of European descent and our group studies a group of ~1400 individuals who descend from 64
founders and are related to each other in a 13 generation pedigree. The Hutterites live communally in the
northern plains states and western Canada. With an extended and well recorded pedigree and technological
advances in sequencing, we can impute Hutterite genotypes with high accuracy and identify the parent of
origin of alleles from 98 Hutterite whole genome sequences to the remaining >1400 individuals in our sample.
In addition to gene expression in LCLs and whole blood, we recorded CVD-association phenotypes for a
subset of this sample that include measurements of lipids (LDL-c, HDL-c, total cholesterol, triglycerides, and
Lp(a)), blood pressure (systolic and diastolic), carotid artery media thickness (CIMT), and echocardiographic
traits (left ventricular mass, left atrial volume, among many others), as well as inflammatory cell counts. With
this unique population resource, we can disentangle the contribution of maternally inherited alleles and
paternally inherited alleles to CVD-associated phenotypes and ultimately to risk for cardiovascular disease.
项目摘要:
该项目的总体目标是评估用于识别遗传变异的新策略,
常见的复杂疾病,特别关注导致心血管疾病(CVD)的变异
风险来自原产地效应。CVD是男性和女性死亡的主要原因,
全基因组关联研究(GWAS)已经确定了一些与CVD风险有关的遗传位点,
仍然未知。GWAS鉴定的风险等位基因几乎不能解释该性状的遗传性,
这种“缺失的遗传力”被归因于父母的起源效应。我建议弥合这一差距,
通过表征亲本来源对基因表达和CVD相关表型的影响来了解
计算哈特人CVD表型的亲本遗传力。哈特派是
欧洲血统的人群,我们的研究小组研究了一组约1400人,他们来自64
他们是13代血统中的创始人,彼此有血缘关系。赫特人共同生活在
北方平原州和加拿大西部。有着广泛的和良好的记录血统和技术
随着测序技术的进步,我们可以高准确度地估算Hutterite基因型,
从98个哈特人全基因组序列到我们样本中剩余的>1400个个体的等位基因起源。
除了LCL和全血中的基因表达外,我们还记录了LCL和全血中的CVD相关表型。
该样本的子集,包括脂质(LDL-c、HDL-c、总胆固醇、甘油三酯和
Lp(a))、血压(收缩压和舒张压)、颈动脉中层厚度(CIMT)和超声心动图
性状(左心室质量,左心房容积等)以及炎症细胞计数。与
这种独特的人口资源,我们可以解开母系遗传等位基因的贡献,
父系遗传的等位基因与心血管疾病相关表型相关,并最终与心血管疾病的风险相关。
项目成果
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