Genetic Analysis Of Non-alzheimer Dementias

非阿尔茨海默痴呆症的遗传分析

• 批准号: 7732372
• 负责人: Andrew Singleton
• 金额: $ 16.11万
• 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/7732372
• 关键词: Aging; Alzheimer' s Disease; Amyloid; Amyotrophic Lateral Sclerosis; Brain; Chromosome Mapping; Chromosomes, Human, Pair 9; Complement; Dementia; Disease; Family; Family history of; Finland; Frontotemporal Dementia; Gene Mutation; Genes; Genetic; Genetic Risk; Individual; Lewy Body Disease; Light; Localized; Maps; Measures; Molecular Genetics; Mutation; Paper; Parkinson Disease; Parkinson' s Dementia; Pathology; Phenotype; Prion Diseases; Progranulin; Publishing; Quantitative Trait Loci; Risk; Series; Work; base; genetic analysis; genome wide association study; neuropathology; non-alzheimer dementia; novel; positional cloning; synuclein; tau Proteins

During this year we have found several families with progranulin mutations and now have papers published and in press on this. This work has shown that progranulin mutations produce a fairly typical phenotype and are not associated with overlapping disorders such as amyotrophic lateral sclerosis. We have used dense SNP based linkage mapping to identify novel loci associated with familial frontotemporal dementia. This work shows linkage overlapping an extant locus on chromosome 9 and we are now involved in a positional cloning project to determine the underlying genetic mutation in this family; this project involves sequencing of approximately 80 genes within the critical interval and is currently 50% complete. Our ongoing work on dementia with Lewy bodies and Parkinson's disease with dementia primarily focuses on analysis of loci identified in our genome wide association studies in Alzheimer's disease and Parkinson's disease to see if we can tease out the genetic basis of dementia in these disorders which neuropathologically sit between Alzheimer's and Parkinson's disease. This work complements our analysis of quantitative neuropathology in a series of brains from a longitudinal aging study from Finland; in particular the analysis of these neuropathological measures in terms of genetic risk - we have performed quantitative trait locus mapping in approximately 250 such brains and identified several loci positively associated with amyloid, tau and synuclein pathologies.

在这一年中，我们发现了几个家庭与颗粒蛋白前体突变，现在有论文发表和出版。这项工作表明，颗粒蛋白前体突变产生一个相当典型的表型，并没有与重叠的疾病，如肌萎缩侧索硬化症。我们已经使用密集的SNP为基础的连锁图谱，以确定新的基因座与家族性额颞叶痴呆。这项工作显示了9号染色体上一个现存位点的连锁重叠，我们现在正在参与一个定位克隆项目，以确定该家族中潜在的遗传突变;该项目涉及在关键间隔内对大约80个基因进行测序，目前已完成50%。 我们正在进行的关于路易体痴呆和帕金森病痴呆的工作主要集中在分析我们在阿尔茨海默病和帕金森病的全基因组关联研究中鉴定的基因座，看看我们是否可以梳理出这些疾病中痴呆的遗传基础，这些疾病在神经病理学上位于阿尔茨海默病和帕金森病之间。这项工作补充了我们对来自芬兰的纵向衰老研究的一系列大脑中的定量神经病理学的分析;特别是对这些神经病理学指标在遗传风险方面的分析-我们已经在大约250个这样的大脑中进行了定量性状基因座作图，并确定了几个与淀粉样蛋白，tau蛋白和突触核蛋白病理学正相关的基因座。

项目成果

Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP.

• DOI: 10.1016/j.neurobiolaging.2008.06.012
• 发表时间: 2010-05
• 期刊: NEUROBIOLOGY OF AGING
• 影响因子: 4.2
• 作者: Guerreiro, Rita Joao;Baquero, Miguel;Blesa, Rafael;Boada, Merce;Bras, Jose Miguel;Bullido, Maria J.;Calado, Ana;Crook, Richard;Ferreira, Carla;Frank, Ana;Gomez-Isla, Teresa;Hernandez, Isabel;Lleo, Alberto;Machado, Alvaro;Martinez-Lage, Pablo;Masdeu, Jose;Molina-Porcel, Laura;Molinuevo, Jose L.;Pastor, Pau;Perez-Tur, Jordi;Relvas, Rute;Oliveira, Catarina Resende;Ribeiro, Maria Helena;Rogaeva, Ekaterina;Sa, Alfredo;Samaranch, Lluis;Sanchez-Valle, Raquel;Santana, Isabel;Tarraga, Lluis;Valdivieso, Fernando;Singleton, Andrew;Hardy, John;Clarimon, Jordi
• 通讯作者: Clarimon, Jordi

The human genome is sequenced: what does it mean and why is it important?

人类基因组已测序：这意味着什么以及为什么它很重要？

• DOI: 10.1001/archneur.58.11.1748
• 发表时间: 2001
• 期刊: Archives of neurology
• 作者: Hardy,J

The relationship between Lewy body disease, Parkinson's disease, and Alzheimer's disease.

路易体病、帕金森病和阿尔茨海默病之间的关系。

• DOI: 10.1111/j.1749-6632.2003.tb07474.x
• 发表时间: 2003
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Hardy,John

Analysis of tau haplotypes in Pick's disease.

皮克病中 tau 单倍型分析。

• DOI: 10.1212/wnl.59.3.443
• 发表时间: 2002
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Morris,HR;Baker,M;Yasojima,K;Houlden,H;Khan,MN;Wood,NW;Hardy,J;Grossman,M;Trojanowski,J;Revesz,T;Bigio,EH;Bergeron,C;Janssen,JC;McGeer,PL;Rossor,MN;Lees,AJ;Lantos,PL;Hutton,M
• 通讯作者: Hutton,M

No evidence for tau duplications in frontal temporal dementia families showing genetic linkage to the tau locus in which tau mutations have not been found.

没有证据表明额颞叶痴呆家族中的 tau 重复与尚未发现 tau 突变的 tau 基因座存在遗传联系。

• DOI: 10.1016/j.neulet.2004.03.070
• 发表时间: 2004
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Johnson,Janel;Ostojic,Jovanka;Lannfelt,Lars;Glaser,Anna;Basun,Hans;Rogaeva,Ekaterina;Kawarai,Toshitaka;Bruni,Amalia;StGeorgeHyslop,PeterH;Goate,Alison;Pastor,Pau;Chakraverty,Sumi;Norton,Joanne;Morris,JohnC;Hardy,John;Sin
• 通讯作者: Sin