Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease
Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease
批准号:
8554751
负责人:
M. Ilyas Kamboh
金额:
$58.49万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-09-30 至 2017-05-31
关键词:
AccountingAffectAgeAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease riskApolipoprotein EBiologicalBrainCandidate Disease GeneCerebellumComplexDNA ResequencingDataDementiaDiseaseEPHA1 geneElderlyEnvironmental Risk FactorFamilyGene ExpressionGene FrequencyGenesGeneticGenetic PolymorphismGenetic VariationGenomeGenotypeGoalsHumanIndividualIntercistronic RegionIntronsJointsLate Onset Alzheimer DiseaseLinkage DisequilibriumMeasuresMedicalModelingNeurodegenerative DisordersPTK2B genePenetrancePhenotypePopulation Attributable RisksPredispositionPrefrontal CortexPublic HealthReportingResearchRiskRisk FactorsSamplingSignal TransductionSingle Nucleotide PolymorphismStagingStructureTemporal LobeTestingUniversitiesUntranslated RegionsVariantapolipoprotein E-4case controldesigndisorder riskfunctional groupgenome wide association studynext generation sequencingpublic health relevancetrait
中文摘要
描述(由申请人提供):阿尔茨海默病(AD),尤其是迟发性(LOAD)是一种复杂的多因素神经退行性疾病,可能涉及几个基因。直到2010年,APOE是LOAD唯一确定的风险因素。然而,最近的五项大型全基因组关联研究(GWAS)已经确定了LOAD与其他九个位点的SNP的显著关联,包括ABCA 7,MS 4A 4,EPHA 1,CLU,CR 1,PICALM,BIN 1,CD 2AP和CD 33,并且除了CR 1和CD 2AP之外的所有位点都在我们的GWAS样本中得到了复制。虽然GWAS在发现LOAD的其他基因方面做出了重大贡献,但它们不太可能识别所有的遗传贡献,因为商业GWAS阵列被设计为仅捕获具有低突变率的常见变异以测试常见疾病/常见变异假设。另一方面,与未被GWAS捕获的常见变异相比,个体变异率更高的罕见变异可能占常见和复杂疾病人群归因风险的1/3,并且多种罕见变异可能占许多观察到的GWAS信号。此外,GWAS阵列使用依赖于连锁不平衡的间接关联方法来检测关联信号,并且很少鉴定出的显著变体是
因果变量这可以解释与观察到的GWAS信号相关的小效应量。在这里,我们建议对最近GWAS中涉及的七个基因区域进行深度重测序,并在我们的样本中复制,并在1,000例AD病例和对照中使用下一代测序选择参与这七个基因网络的其他基因,以识别常见和罕见的SNP,并在独立样本中复制它们。在这些基因中的因果变异的鉴定将在理解LOAD的潜在生物学机制方面做出重大贡献。
英文摘要
DESCRIPTION (provided by applicant): Alzheimer's disease (AD), especially late-onset (LOAD) is a complex multifactorial neurodegenerative disease with the possible involvement of several genes. Until 2010, APOE was the only established risk factor for LOAD. However, recent five large genomewide association studies (GWAS) have identified significant associations of LOAD with SNPs in nine additional loci, including, ABCA7, MS4A4, EPHA1, CLU, CR1, PICALM, BIN1, CD2AP and CD33 and all, but CR1 and CD2AP, have been replicated in our GWAS sample. Although GWAS have made significant contribution in uncovering additional genes for LOAD, they are unlikely to identify all the genetic contribution because the commercial GWAS arrays are designed to capture only the common variants with low penetrance to test common disease/common variant hypothesis. On the other hand, rare variants having a higher individual penetrance than common variants that are not captured by GWAS may account for 1/3 of the population attributable risk for common and complex diseases and multiple rare variants may account for many of the observed GWAS signals. Furthermore, GWAS arrays use an indirect approach of association that relies on linkage disequilibrium to detect association signals and rarely the identified significant variants are the
causal variants. This may explain the small effect sizes associated with the observed GWAS signals. Here we propose to perform deep resequencing of the seven gene regions implicated in recent GWAS and replicated in our sample and selected additional genes involved in the networks of these seven genes using next-generation sequencing in 1,000 AD cases and controls to identify both common and rare SNPs and replicate them in independent samples. The identification of causal variants in these genes would make a significant contribution in understanding the underlying biological mechanism of LOAD.
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会议论文
Biomarker and Neurogenetics Core
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批准号:10590714
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项目类别:
-
资助金额:$32.21万
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财政年份:2020
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负责人:M. Ilyas Kamboh
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依托单位:
Biomarker and Neurogenetics Core
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批准号:10410387
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项目类别:
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资助金额:$26.44万
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财政年份:2020
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负责人:M. Ilyas Kamboh
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依托单位:
Biomarker and Neurogenetics Core
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批准号:10161692
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项目类别:
-
资助金额:$26.17万
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财政年份:2020
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负责人:M. Ilyas Kamboh
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依托单位:
Search for the Alzheimers Genes
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批准号:9190589
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项目类别:
-
资助金额:$15.4万
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财政年份:2016
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负责人:M. Ilyas Kamboh
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依托单位:
Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease
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批准号:8435118
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项目类别:
-
资助金额:$62.51万
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财政年份:2012
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负责人:M. Ilyas Kamboh
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依托单位:
Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease
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批准号:8721824
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项目类别:
-
资助金额:$61.65万
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财政年份:2012
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负责人:M. Ilyas Kamboh
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依托单位:
Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease
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批准号:9094395
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项目类别:
-
资助金额:$59.51万
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财政年份:2012
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负责人:M. Ilyas Kamboh
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依托单位:
Search for the Alzheimer's Gene on Chromosome 10
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批准号:8217122
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项目类别:
-
资助金额:$66.56万
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财政年份:2010
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负责人:M. Ilyas Kamboh
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依托单位:
Search for the Alzheimer's Gene on Chromosome 10
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批准号:8423754
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项目类别:
-
资助金额:$61.97万
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财政年份:2010
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负责人:M. Ilyas Kamboh
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依托单位:
Search for the Alzheimer's Gene on Chromosome 10
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批准号:8030415
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项目类别:
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资助金额:$72.91万
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财政年份:2010
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负责人:M. Ilyas Kamboh
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依托单位:
Search for the Alzheimer's Gene on Chromosome 10
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批准号:7762196
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项目类别:
-
资助金额:$74.83万
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财政年份:2010
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负责人:M. Ilyas Kamboh
-
依托单位:
Search for the Alzheimer's Gene on Chromosome 10
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批准号:7577259
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项目类别:
-
资助金额:$77.25万
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财政年份:2009
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负责人:M. Ilyas Kamboh
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依托单位:
Search for the Alzheimers Genes
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批准号:9283293
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项目类别:
-
资助金额:$76.44万
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财政年份:2009
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负责人:M. Ilyas Kamboh
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依托单位:
Search for the Alzheimers Genes
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批准号:8962827
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项目类别:
-
资助金额:$75.77万
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财政年份:2009
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负责人:M. Ilyas Kamboh
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依托单位:
Search for the Alzheimers Genes
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批准号:9130068
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项目类别:
-
资助金额:$75.77万
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财政年份:2009
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负责人:M. Ilyas Kamboh
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依托单位:
Immune/Inflammation Genomics and the Risk of SLE and CHD
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批准号:7581725
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项目类别:
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资助金额:$75.73万
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财政年份:2008
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负责人:M. Ilyas Kamboh
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依托单位:
Immune/Inflammation Genomics and the Risk of SLE and CHD
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批准号:8011108
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项目类别:
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资助金额:$5.17万
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财政年份:2008
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负责人:M. Ilyas Kamboh
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依托单位:
Immune/Inflammation Genomics and the Risk of SLE and CHD
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批准号:7996628
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项目类别:
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资助金额:$63.05万
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财政年份:2008
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负责人:M. Ilyas Kamboh
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依托单位:
Immune/Inflammation Genomics and the Risk of SLE and CHD
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批准号:8204772
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项目类别:
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资助金额:$62.99万
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财政年份:2008
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负责人:M. Ilyas Kamboh
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依托单位:
Immune/Inflammation Genomics and the Risk of SLE and CHD
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批准号:7744034
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项目类别:
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资助金额:$68.37万
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财政年份:2008
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负责人:M. Ilyas Kamboh
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依托单位:
海外基金