Genetics of Alzheimer's Disease in Mexico

墨西哥阿尔茨海默病的遗传学

• 批准号: 9789145
• 负责人: Sandra Barral Rodriguez
• 金额: $ 226.94万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789145
• 关键词: Address; Adult; Affect; African; African American; Age; Age-Years; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Automobile Driving; Caribbean Hispanic; Caribbean region; Cells; Classification; Clinical; Clinical Data; Clinical Research; Clinical assessments; Cognitive; Cohort Studies; Collection; Communities; Counseling; DNA; Data; Dementia; Diagnosis; Disease; Ensure; Ethnic group; Evaluation; Family; Family Study; Follow-Up Studies; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genetic Variation; Genetic screening method; Genetic study; Genome; Genomics; Genotype; Goals; Health; Health and Retirement Study; High Prevalence; Impaired cognition; Incidence; Individual; International; Interview; Investigation; Late Onset Alzheimer Disease; Longitudinal Studies; Mexican; Mexico; Minority; National Institute on Aging; Nerve Degeneration; Neurodegenerative Disorders; Neuropsychological Tests; Neuropsychology; Not Hispanic or Latino; Participant; Pathway interactions; Persons; Phenotype; Population; Population Heterogeneity; Population Study; Prevalence; Prevention; Quality Control; Race; Recommendation; Research; Risk; Saliva; Sampling; Study Subject; Translational Research; United States; Variant; Washington; admixture mapping; age related; aged; base; case control; clinical Diagnosis; cognitive testing; cohort; design; disorder prevention; endophenotype; ethnic diversity; falls; follow-up; genetic risk factor; genetic variant; genome sequencing; genome wide association study; member; novel; precision medicine; prospective; repository; rural setting; socioeconomics; urban setting; whole genome

Late onset Alzheimer’s disease (LOAD) with onset after age 60 years is the most frequent neurodegenerative disease affecting all ethnic and racial groups. Although the causes remain unclear, studies in case-control cohorts and families with multiple affected members support a genetic etiology for LOAD. To date, large genome- wide association (GWAS) and sequencing studies of LOAD have been carried out mostly in non-Hispanic White populations, and have so far identified over 21 loci associated with increased risk of LOAD. The same loci have also been identified in ethnically diverse populations (Caribbean-Hispanics and African-Americans), some of them with even large genetic effects such as ABCA7 in African Americans. Novel genes were also discovered by GWAS in non-White populations (e.g. FBXL7 in Caribbean Hispanics), ultimately proving their potential to reveal novel pathways or mechanisms underlying LOAD risk and prevention. Data from the 10/66 Dementia Research Group estimates the prevalence of dementia in Mexico to be ~7.3% for people 60 years of age and older, and is projected to increase up to 400% by 2050. Despite this high prevalence, Mexican population is underrepresented in genetic studies. To our knowledge, other than APOE gene effect on the disease, there are few genetic investigations of LOAD among individuals of Mexican ancestry in the United States or elsewhere. The underrepresentation of individuals of Mexican and other ancestries in genetic and translational research ultimately affects the possibility of leveraging their contribution on clinical genomic applications such as genetic testing, counseling and ultimately precision medicine approaches. We aim to define risk and protective genetic loci on LOAD and related dementias in individuals with Mexican ancestry. To that end, the proposed study will establish the first large-scale investigation of the genetic bases for LOAD and related disorders among individuals of Mexican ancestry. We propose to build on an existing unique and outstanding cohort, the “Mexican Health and Aging Study” (MHAS); this is a prospective national longitudinal study, which began in 2001, has aimed to evaluate the impact of age-related diseases among Mexican adults living in both urban and rural settings. Over a 20-years follow-up, MHAS has collected demographic and clinical data (including cognitive assessment) in 15,000 individuals of Mexican ancestry aged 50 and older. Specifically we propose to: 1) obtain saliva in all MHAS participants over age 60 years who will be interview in the fall of 2018 as part of the 5th MHAS follow-up wave, and perform a genome wide association study (GWAS) and admixture mapping for dementia using DNA extracted from ~10,000 participants. 2) validate clinical dementia classification with an extended cognitive Mex-Cog battery in a sub-sample of ~2500 MHAS participants 60 years of age or older to be consistent with NIA-Alzheimer Association recommendations; this will also be used to validate the clinical diagnoses used for the GWAS in the previous aim. 3) perform whole genome sequencing in the subsample of MHAS subjects with validated diagnosis.

晚发性阿尔茨海默病（LOAD）是60岁以后发病的最常见的神经退行性疾病， 影响所有种族和民族的疾病。尽管病因尚不清楚，但病例对照研究表明， 有多个受影响成员的队列和家庭支持LOAD的遗传病因。到目前为止，大型基因组- LOAD的广泛关联（GWAS）和测序研究主要在非西班牙裔白色人中进行 人群中，迄今已确定超过21个位点与LOAD的风险增加。同样的基因座 在不同种族的人群（加勒比-西班牙裔和非洲裔美国人）中也发现了这种情况， 他们甚至有很大的遗传效应，如ABCA 7在非洲裔美国人。新的基因也被发现 GWAS在非白人人群中（例如，FBXL 7在加勒比海西班牙裔人群中），最终证明了它们的潜力， 揭示LOAD风险和预防的新途径或机制。 来自10/66痴呆症研究小组的数据估计， 60岁及以上的人，预计到2050年将增加400%。尽管患病率很高， 墨西哥人口在遗传学研究中的代表性不足。据我们所知，除了APOE基因对 虽然这种疾病，但在美国墨西哥血统的个体中很少有LOAD的遗传调查 国家或其他地方。墨西哥和其他血统的人在遗传和 转化研究最终会影响他们对临床基因组学的贡献 例如基因检测、咨询和最终的精准医疗方法。 我们的目标是确定墨西哥痴呆症患者LOAD和相关痴呆症的风险和保护性遗传位点。 祖先为此，拟议的研究将建立第一个大规模的遗传基础调查， LOAD和墨西哥血统个体的相关疾病。我们建议建立在现有的独特的 和杰出的队列，“墨西哥健康和老龄化研究”（MHAS）;这是一个前瞻性的国家纵向研究。 一项始于2001年的研究旨在评估与年龄有关的疾病对墨西哥成年人的影响 生活在城市和农村环境中。经过20年的随访，MHAS收集了人口统计学和临床资料， 数据（包括认知评估）在15，000名墨西哥血统的50岁及以上的人。 具体来说，我们建议：1）获取所有年龄超过60岁的MHAS参与者的唾液，这些参与者将在 2018年秋季，作为第五次MHAS后续浪潮的一部分，并进行全基因组关联研究（GWAS） 以及使用从约10，000名参与者中提取的DNA进行痴呆症的混合映射。2)临床验证 在约2500名MHAS参与者的子样本中使用扩展认知Mex-Cog组合进行痴呆分类 60岁或60岁以上的老年人与NIA阿尔茨海默病协会的建议一致;这也将是 用于验证先前目标中用于GWAS的临床诊断。3)进行全基因组 在具有经验证的诊断的MHAS受试者的子样本中进行测序。