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: 8459411
• 负责人: RICHARD P MAYEUX
• 金额: $ 75.86万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459411
• 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; Data; Data Set; Development; Disease; Disease Progression; Disease susceptibility; EPHA1 gene; Epidemiology; Family; Family Study; Family member; Gene Cluster; Gene Mutation; 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; Performance; 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; cohort; disorder risk; endophenotype; exome sequencing; follow-up; 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(由申请者提供)：目前研究诸如迟发性阿尔茨海默病(LOAD)等复杂疾病的遗传影响的基本主题是“共同疾病，共同变异”假说。这一理论认为，多个共同的变种是造成负荷的原因。该项目的目标是验证和量化这些新发现的遗传风险因素的临床影响，即PICALM、CLU、BIN1、MS4A基因簇、CD33、CD2AP、ABCA7和EPHA1中的SNPs，使用通过国家老龄化-晚发性阿尔茨海默病家族研究(NIA-LOAD)招募的多个家庭。在这些家族中丰富的表型和分子遗传信息的可获得性使我们处于独特的地位，可以估计这些变异体和最近GWA荟萃分析和目前正在进行的外显子组测序项目中确定的其他变异体的基因相对风险。拟议的纵向跟踪、确定先前风险因素的额外亲属的特征以及招募尸检也将极大地有利于 扩大NIA-LOAD家庭研究的科学价值。这一家族资源为确定基因变异对疾病风险的影响提供了明显的优势。首先，多基因家庭可能会丰富与风险增加相关的基因变异，从而提供更大的统计能力来估计影响。其次，对这些家系的分析提供了对其余未知遗传影响(即“残留遗传力”)的洞察，以及与已识别的遗传变异相互作用以影响疾病风险的先行修饰因素。第三，定期跟踪有风险的家庭成员，便于前瞻性调查基因变异对发病年龄的影响，以及先前风险和保护因素的修改效果。最后，家庭数据可以提供有关已知变异对疾病进展速度和疾病进展的剩余遗传力的影响的信息。我们将解决两个总体假设：1)晚发性阿尔茨海默病的风险因家庭而异，并与遗传有关 特定的基因变异。在多胎家庭中，这些变异对疾病风险的影响比在零星病例中更大。家系中的表观表现和不完全外显与改变危险因素有关。2)疾病进展速度受基因影响，并与影响疾病易感性的相同基因变异有关。