Genomic Convergence in Alzheimer Disease

阿尔茨海默病的基因组趋同

• 批准号: 8235827
• 负责人: Margaret A. Pericak-Vance
• 金额: $ 113.68万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235827
• 关键词: Advocate; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Candidate Disease Gene; Clinic; Clinical; Clinical Data; Complement; Complex; Data; Data Analyses; Data Set; Development; Disease; Disease susceptibility; Early treatment; Etiology; Evaluation; Family; Floods; Future; Gene Expression; Genes; Genetic; Genetic Epistasis; Genetic Predisposition to Disease; Genome; Genomics; Genotype; Glutathione S-Transferase; Heterogeneity; Individual; Intervention; Joints; Knowledge; Literature; Methods; Modeling; Molecular; Molecular Genetics; Movement; National Institute of Mental Health; Neurodegenerative Disorders; Patients; Positioning Attribute; Predisposition; Process; Publications; Publishing; Risk; Risk Factors; Running; Solutions; Susceptibility Gene; Symptoms; Technology; Testing; Variant; base; case control; clinical phenotype; falls; follow-up; genetic linkage; genome wide association study; genome-wide; innovation; interest; novel strategies; research study; serial analysis of gene expression

DESCRIPTION (provided by applicant): In the past, the field of Alzheimer disease (AD) genetics has benefited from the development of innovative paradigms that incorporate the latest genomic technologies combined with pristine patient data to dissect its complex etiology. Our group has successfully used this paradigm in both the identification of the APOE risk effect and more recently the glutathione S-transferase Omega-1 (GSTO1) age at onset (AAO) effect in AD. There is a new appreciation of the power of incorporating clinical phenotypes and developing clinical subphenotypes in attacking complex disorders. In addition, molecular genetic methods have continued to advance rapidly. Whole genome association (WGA) is a new approach that allows the direct evaluation of 300,000- 1,000,000 SNPs from across the genome for association with AD and provides the opportunity to perform a much more detailed examination of the genome than linkage studies. However, while the information content of WGA is extraordinarily high, the initial false positive rate using standard analyses is also high. Investigating each of the thousands of markers that will reach nominal significance is an ominous and inefficient task. One solution to this problem is the genomic convergence approach, which integrates disparate data types to sift through the volumes of existing data to prioritize the best candidate genes for intensive analysis. We have already demonstrated the utility of this approach with the identification of the GSTO1 gene. Thus we are proposing a WGA study of AD and will filter the results using existing linkage, candidate gene, and our recently generated microarray and Serial Analysis of Gene Expression (SAGE) data. A small set of candidate genes identified in multiple of these studies will be the focus of intensive follow-up analysis. Of particular importance will be our ability to follow-up using detailed clinical data on movement and psychiatric symptoms in a newly collected case-control dataset. Our unique position will enable us to marry the most powerful of new genomic approaches, WGA, to existing information to elucidate additional genetic effects contributing to this important neurodegenerative disease. The knowledge derived from this study will further our understanding of AD and will be crucial for future studies to develop and evaluate interventions. The knowledge derived from this study will further our understanding of the genetic etiology of AD. This understanding will be crucial for future studies to develop early interventions and more focused treatments, which will help alleviate the suffering of those with the disease and their families.

描述（由申请人提供）：过去，阿尔茨海默氏病（AD）遗传学领域受益于创新范式的发展，这些范式结合了最新的基因组技术与原始患者数据相结合以剖析其复杂的病因。我们的小组在APOE风险效应的鉴定和谷胱甘肽S-转移酶Omega-1（GSTO1）年龄（AAO）效应中成功使用了该范式。人们对融合临床表型并在攻击复杂疾病中发展临床亚表征的力量有了新的认识。此外，分子遗传学方法继续迅速发展。整个基因组关联（WGA）是一种新方法，可以在整个基因组中直接评估300,000-1,000,000个SNP，以与AD关联，并提供了与链接研究更详细的对基因组进行更详细的检查的机会。但是，尽管WGA的信息内容非常高，但使用标准分析的初始假阳性率也很高。研究将达到名义意义的数千个标记中的每一个都是不祥效率低下的任务。解决此问题的一种解决方案是基因组收敛方法，该方法将不同的数据类型集成到筛选现有数据的量，以优先考虑最佳候选基因进行密集分析。我们已经通过识别GSTO1基因证明了这种方法的实用性。因此，我们提出了对AD的WGA研究，并将使用现有的链接，候选基因以及我们最近生成的微阵列和基因表达（SAGE）数据的序列分析过滤结果。在这些研究的多个研究中鉴定出的一小部分候选基因将是密集后续分析的重点。特别重要的是，我们有能力在新收集的病例对照数据集中使用有关运动和精神病症状的详细临床数据进行跟进。我们独特的立场将使我们能够将最强大的新基因组方法（WGA）结合到现有信息，以阐明有助于这种重要的神经退行性疾病的其他遗传效应。从这项研究中得出的知识将进一步我们对AD的理解，对于未来的研究以制定和评估干预措施至关重要。从这项研究中得出的知识将进一步了解我们对AD遗传病因的理解。这种理解对于未来的研究至关重要，以制定早期干预措施和更集中的治疗，这将有助于减轻患有疾病及其家人的苦难。

项目成果

Rare Variants and Transcriptomics in Alzheimer disease.

• DOI: 10.1007/s40142-014-0035-9
• 发表时间: 2014-06-01
• 期刊: Current genetic medicine reports
• 影响因子: 2.1
• 作者: Humphries C;Kohli MA
• 通讯作者: Kohli MA

Alzheimer disease (AD) specific transcription, DNA methylation and splicing in twenty AD associated loci.

• DOI: 10.1016/j.mcn.2015.05.003
• 发表时间: 2015-07
• 期刊: Molecular and cellular neurosciences
• 作者: Humphries C;Kohli MA;Whitehead P;Mash DC;Pericak-Vance MA;Gilbert J
• 通讯作者: Gilbert J