Multi-ethnic Genome-wide Alzheimer association study

多种族全基因组阿尔茨海默病关联研究

• 批准号: 7101367
• 负责人: Lindsay A. Farrer
• 金额: $ 42.6万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101367
• 关键词: African American; Alzheimer' s disease; animal data; apolipoprotein E; biochemical evolution; biotechnology; caucasian American; clinical research; computational biology; family genetics; gene environment interaction; genetic mapping; genetic screening; genetic susceptibility; genotype; high throughput technology; human data; human genetic material tag; human tissue; linkage mapping; mass spectrometry; racial /ethnic difference; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) causes severe cognitive and social impairment and is the most common cause of dementia in the elderly, affecting approximately five million people in the United States and 30 million people worldwide. Three highly penetrant genes have been identified that can harbor mutations causing most Mendelian forms of AD, although such familial cases account for only 5% of the AD burden in the population. For the remaining sporadic cases of AD, the e4 allele of the APOE gene has been identified as the most important genetic risk factor. However, over one-third of AD patients lack the e4 allele and less than one third of e4 heterozygotes surviving to age 80 years develop AD, implying that other genetic and environmental risk factors influence AD susceptibility. Several candidate genes have been evaluated to assess their role in AD, but none have been confirmed as having an impact on AD risk. The research proposed herein will use a well-characterized collection of unrelated Caucasian and African American AD cases and non-demented, age-matched controls to carry out a large-scale association study using 100,000 single nucleotide polymorphisms (SNPs) located within 34,237 (96%) of known or predicted genes. This study will employ a cost effective, high-throughput method of SNP analysis that relies on DNA pooling and chip-based mass spectrometry to compare allele frequencies among AD cases having at least one e4 allele, AD cases lacking e4, and non-demented controls. This design will allow us to identify genes that influence 1) overall risk of AD and 2) risk of AD in the presence or absence of e4. Results for the most strongly associated SNPs will be verified by genotyping. In subsequent steps, genetic associations will be verified by replication in an independent collection of AD cases and controls and discordant sibships, and elaborated by targeted SNP discovery and haplotype analysis in conserved genomic regions.

描述（由申请人提供）：阿尔茨海默病 (AD) 会导致严重的认知和社交障碍，是老年人痴呆症的最常见原因，影响着美国约 500 万人和全球约 3000 万人。已经确定了三种高渗透性基因，它们可能含有导致大多数孟德尔形式 AD 的突变，尽管此类家族病例仅占人口 AD 负担的 5%。对于其余散发性 AD 病例，APOE 基因的 e4 等位基因已被确定为最重要的遗传风险因素。然而，超过三分之一的 AD 患者缺乏 e4 等位基因，并且存活到 80 岁的 e4 杂合子中不到三分之一会患 AD，这意味着其他遗传和环境风险因素也会影响 AD 易感性。已经对几个候选基因进行了评估，以评估它们在 AD 中的作用，但没有一个基因被证实对 AD 风险有影响。本文提出的研究将使用一组经过充分表征的不相关的白种人和非裔美国人 AD 病例以及非痴呆、年龄匹配的对照，利用位于 34,237 个国家（96 %) 已知或预测的基因。这项研究将采用一种经济高效、高通量的 SNP 分析方法，该方法依靠 DNA 池和基于芯片的质谱分析来比较具有至少一个 e4 等位基因的 AD 病例、缺乏 e4 的 AD 病例和非痴呆对照之间的等位基因频率。该设计将使我们能够识别影响 1) AD 总体风险和 2) 在存在或不存在 e4 的情况下影响 AD 风险的基因。相关性最强的 SNP 的结果将通过基因分型进行验证。在后续步骤中，将通过在 AD 病例和对照以及不一致同胞关系的独立集合中进行复制来验证遗传关联，并通过保守基因组区域中的目标 SNP 发现和单倍型分析来详细阐述。