Epidemiology of Familial Late-Onset Alzheimer's Disease

家族性晚发性阿尔茨海默病的流行病学

• 批准号: 8827233
• 负责人: RICHARD P MAYEUX
• 金额: $ 82.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827233
• 关键词: Accounting; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Autopsy; Cardiovascular system; Cerebrovascular Disorders; Clinical; Clinical assessments; Clinical dementia rating scale; Cognitive; Complex; DNA Sequence Alteration; Data; Data Set; Development; Disease; Disease Progression; Disease susceptibility; EPHA1 gene; Epidemiology; Family; Family Study; Family member; Gene Cluster; Genes; Genetic; Genetic Research; Genetic Risk; Genotype; Goals; Heritability; Individual; Investigation; Late Onset Alzheimer Disease; Measures; Mental disorders; Meta-Analysis; Molecular Genetics; Mutation; National Institute on Aging; Other Genetics; Patients; Penetrance; Phenocopy; Physical activity; Positioning Attribute; Principal Investigator; Public Health; Recommendation; Recruitment Activity; Recurrence; Relative (related person); Relative Risks; Residual state; Resources; Risk; Risk Estimate; Risk Factors; Single Nucleotide Polymorphism; Subgroup; Telephone; Telephone Interviews; Testing; Time; Variant; case control; cognitive performance; cohort; disorder risk; endophenotype; exome sequencing; follow-up; genetic information; genetic pedigree; genetic risk factor; genetic variant; genome wide association study; high risk; improved; insight; presenilin-1; programs; prospective; risk variant; screening; theories

DESCRIPTION (provided by applicant): A current theme underlying research for genetic influences in complex diseases such as late onset Alzheimer's disease (LOAD) is the "common disease, common variant" hypotheses. This theory posits that multiple common variants underlie the cause of LOAD. The goals of this project is to validate and quantify the clinical impact of these newly identified genetic risk factors, namely SNPs in PICALM, CLU, BIN1, MS4A gene clusters, CD33, CD2AP, ABCA7 and EPHA1 using the multiplex families recruited through the National Institute on Aging-Late Onset Alzheimer's Disease Family Study (NIA-LOAD). The availability of rich phenotypic and molecular genetic information in these families places us in a unique position to estimate the genotype relative risks for these variants and others identified in the recent GWA meta-analyses and the exome sequencing projects currently underway. The proposed longitudinal follow-up, the characterization of additional relatives with ascertainment of antecedent risk factors, and recruitment for autopsy will also greatly benefit the field by expanding the scientific value of the NIA-LOAD Family Study. This resource of families provides distinct advantages for characterizing the impact of genetic variants on disease risk. First, multiplex families are likely to be enriched for genetic variants associated with increased risk, providing increased statistical power to estimate the effects. Second, analysis of these families provides insight into the remaining unknown genetic influences (i.e., the "residual heritability) as well as antecedent modifying factors that interact with identified genetic variant to influence disease risk. Third, family members at risk are followed at regular intervals, facilitating prospective investigation of the effects of the genetic variants on age-at-onset as wel as the modifying effects of antecedent risk and protective factors. Finally, family data can provide information regarding the influence of known variants on the rate of disease progression and the residual heritability of disease progression. We will address two overall hypotheses: 1) the risk of late onset Alzheimer's disease differs among families and is related to the inheritance of specific genetic variants. The impact of these variants on disease risk is greater in multiplex families than in sporadic cases. Phenocopies and incomplete penetrance in families are related to modifying risk factors. 2) The rate of disease progression is genetically influenced, and related to the same genetic variants that influence disease susceptibility.

描述（由申请人提供）：目前的主题是针对复杂疾病（如晚期阿尔茨海默氏病）（负载）等复杂疾病的遗传影响的基础研究。该理论认为，多种常见变体是负载原因的基础。该项目的目标是验证和量化这些新鉴定的遗传危险因素的临床影响，即Picalm，Clu，Bin1，MS4A基因组，CD33，CD33，CD2AP，ABCA7和EPHA1使用多重多重家族通过通过国立ALZHEIMERIMER EASERY的ALZHEIMERES DELASE招募的多重多重家族（NIA）。在这些家庭中，丰富的表型和分子遗传信息的可用性使我们处于独特的位置，以估计这些变体的基因型相对风险以及最近正在进行的GWA荟萃分析和目前正在进行的外显子组测序项目中所鉴定的其他位置。拟议的纵向随访，通过确定先决危险因素的其他亲戚的表征以及尸检的招募也将极大地受益 通过扩大NIA负载家庭研究的科学价值来领域。家庭资源为表征遗传变异对疾病风险的影响提供了明显的优势。首先，多重家族可能会富含与风险增加有关的遗传变异，从而增加统计能力以估计影响。 Second, analysis of these families provides insight into the remaining unknown genetic influences (i.e., the "residual heritability) as well as antecedent modifying factors that interact with identified genetic variant to influence disease risk. Third, family members at risk are followed at regular intervals, facilitating prospective investigation of the effects of the genetic variants on age-at-onset as wel as the modifying effects of antecedent risk and protective factors. Finally, family data可以提供有关已知变异对疾病进展率的影响和疾病进展的残留遗传力的影响。 特定的遗传变异。这些变体对疾病风险的影响比零星的病例更大。家族的表托和不完整的渗透与改变的危险因素有关。 2）疾病进展的速度受到遗传影响，并且与影响疾病易感性的相同遗传变异有关。