Genetic Analysis Of Alzheimer s Disease

阿尔茨海默病的基因分析

• 批准号: 7732371
• 负责人: Andrew Singleton
• 金额: $ 42.96万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732371
• 关键词: Alzheimer' s Disease; Brain; Clinical; Collaborations; Consanguinity; DNA Resequencing; Data; Dementia; Disease; Family; Generations; Genes; Genetic; Genetic Risk; Genome; Genomics; Genotype; Goals; Intervention; Laboratories; Lead; Maps; Mutation; Pathogenicity; Pathway interactions; Phase; Phenotype; Population; Public Domains; Publishing; Quantitative Trait Loci; Reporting; Risk; Risk Factors; Role; SNP genotyping; Sampling; Work; base; density; genetic analysis; genetic risk factor; genome wide association study; insight; neurogenetics; novel; presenilin; presenilin-1; presenilin-2

In collaboration with translational genomics a genome wide association analysis in Alzheimers disease was completed, this work involved generation and analysis of more than 1/2 billion genotypes; and these analyses have now been released into the public domain. This work showed elegantly that the APO E locus is the single over-riding common genetic risk factor for Alzheimers disease. Subsequent analysis revealed a potential role for genetic variability in GAB2-A as a novel risk factor in Alzheimers disease. In addition to this work we have begun collecting related phenotypes (for eg dementia) from subjects genotyped by genome wide SNP association and from neurologically normal controls also genotyped within the laboratory in order to increase the power of the initial study. A subset of the samples involved in the genome wide association study were collected by the laboratory of neurogenetics from brain banks; generation of expression data in these Alzheimer's disease samples was performed last year and these data are currently being analyzed and compared to similar data in control samples in an attempt to produce an expression quantitative trait locus map of the Alzheimer's disease brain and to potentially identify a genetic basis of expression differences observed between brains from neurologically normal subjects and those with Alzheimer's disease. Resequencing analysis of APP and presenilin genes in novel disease populations has lead to new insights into the potential pathogenicity previously reported presenilin-1 and presenilin-2 mutations. In addition we are analyzing young-onset samples without known mutations and families where parental consanguinity is suspected using dense SNP genotyping in an attempt to identify novel recessive loci for Alzheimer's disease, the first portion of this work was published this year and a second phase, involving a larger young-onset but outbred population, is ongoing.

与翻译基因组学合作，完成了阿尔茨海默病的全基因组关联分析，这项工作涉及超过二分之一基因型的生成和分析；这些分析现已发布到公共领域。这项工作巧妙地表明，APO E 基因座是阿尔茨海默病唯一最重要的常见遗传风险因素。随后的分析揭示了 GAB2-A 遗传变异作为阿尔茨海默病新危险因素的潜在作用。除了这项工作之外，我们还开始从通过全基因组 SNP 关联进行基因分型的受试者和也在实验室内进行基因分型的神经系统正常对照中收集相关表型（例如痴呆），以提高初始研究的效力。 神经遗传学实验室从脑库中收集了参与全基因组关联研究的样本子集；去年，我们在这些阿尔茨海默病样本中生成了表达数据，目前正在对这些数据进行分析，并与对照样本中的类似数据进行比较，试图生成阿尔茨海默病大脑的表达数量性状基因座图，并潜在地确定神经系统正常受试者和阿尔茨海默病患者大脑之间观察到的表达差异的遗传基础。 对新疾病人群中的 APP 和早老素基因进行重测序分析，对先前报道的早老素 1 和早老素 2 突变的潜在致病性有了新的认识。此外，我们正在分析没有已知突变的年轻发病样本和怀疑父母近亲血亲的家庭，使用密集的 SNP 基因分型，试图识别阿尔茨海默病的新隐性位点，这项工作的第一部分已于今年发表，第二阶段正在进行中，涉及更大的年轻发病但近亲繁殖的人群。

项目成果

Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk.

• DOI: 10.1001/jamaneurol.2013.448
• 发表时间: 2013-10
• 期刊: JAMA neurology
• 影响因子: 29
• 作者: Moskvina V;Harold D;Russo G;Vedernikov A;Sharma M;Saad M;Holmans P;Bras JM;Bettella F;Keller MF;Nicolaou N;Simón-Sánchez J;Gibbs JR;Schulte C;Durr A;Guerreiro R;Hernandez D;Brice A;Stefánsson H;Majamaa K;Gasser T;Heutink P;Wood N;Martinez M;Singleton AB;Nalls MA;Hardy J;Owen MJ;O'Donovan MC;Williams J;Morris HR;Williams NM;IPDGC and GERAD Investigators
• 通讯作者: IPDGC and GERAD Investigators

The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE.

• DOI: 10.1016/j.neurobiolaging.2010.03.025
• 发表时间: 2012-03
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Guerreiro RJ;Gustafson DR;Hardy J
• 通讯作者: Hardy J

Has the amyloid cascade hypothesis for Alzheimer's disease been proved?

• DOI: 10.2174/156720506775697098
• 发表时间: 2006-02-01
• 期刊: Current Alzheimer Research
• 影响因子: 2.1
• 作者: Hardy, John

Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal.

• DOI: 10.3233/jad-2006-9s317
• 发表时间: 2006
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: J. Hardy

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

• DOI: 10.1371/journal.pone.0013950
• 发表时间: 2010-11-15
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Jones L;Holmans PA;Hamshere ML;Harold D;Moskvina V;Ivanov D;Pocklington A;Abraham R;Hollingworth P;Sims R;Gerrish A;Pahwa JS;Jones N;Stretton A;Morgan AR;Lovestone S;Powell J;Proitsi P;Lupton MK;Brayne C;Rubinsztein DC;Gill M;Lawlor B;Lynch A;Morgan K;Brown KS;Passmore PA;Craig D;McGuinness B;Todd S;Holmes C;Mann D;Smith AD;Love S;Kehoe PG;Mead S;Fox N;Rossor M;Collinge J;Maier W;Jessen F;Schürmann B;Heun R;Kölsch H;van den Bussche H;Heuser I;Peters O;Kornhuber J;Wiltfang J;Dichgans M;Frölich L;Hampel H;Hüll M;Rujescu D;Goate AM;Kauwe JS;Cruchaga C;Nowotny P;Morris JC;Mayo K;Livingston G;Bass NJ;Gurling H;McQuillin A;Gwilliam R;Deloukas P;Al-Chalabi A;Shaw CE;Singleton AB;Guerreiro R;Mühleisen TW;Nöthen MM;Moebus S;Jöckel KH;Klopp N;Wichmann HE;Rüther E;Carrasquillo MM;Pankratz VS;Younkin SG;Hardy J;O'Donovan MC;Owen MJ;Williams J
• 通讯作者: Williams J