Grant Detail
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Identification and Characterization of Novel AD Genes
1 April 1999 - 30 April 2013
NATIONAL INSTITUTE OF MENTAL HEALTH
Total Funding: $ 6,038,073
Since 1989, we have led the ascertainment,evaluation, and genetic analysesof the NIMH GeneticsInitiative Alzheimer's disease (AD) sample. This set of AD families, which currently includes 457 families, is the argest uniformly ascertained and evaluated sample assembled for the study of AD genetics. Over the first ive years of this R37, we have continued to carry out genetic analysesand follow-up studies of our a high- resolution whole genome genetic linkage screen for novel AD candidate genes. We have focused on linkage peaks identified on chromosomes 9 and 10, and identified late-onsetAD candidate genes in both ofthese inkage peaks: insulin degrading enzyme (IDE;10q) and ubiquilin 1 (UBQLN1;9q). In addition tofunctionally characterizing these genes for potential pathogenic effects in AD, we have built a highly efficient gene discovery pipeline, customized for large-scale generation, confirmation, storage and analysis of SNP genotype information. Our NIMH family-based association database of positional candidate gene contains over 500,000 genotypes for more than 300 SNPs in over 150 genestested in the full NIMH sample. Furthermore, we have recently obtained nearly one billion genotypes for the NIMH sample from a high- density, whole genome association screen using the Affymetrix 500K SNPchip, currently under analysis. By early October, we will also have obtained the results of a screen of the Affymetrix20,000 coding region SNPs (cSNPs) for the entire NIMH AD family sample. This screen should identify SNPs with a higher probability of potentially pathologenic effects.These combined data sets now provide anunprecedented array of AD candidate genes collectively accounting for as much as 95% of the genetic van'ability of AD. In the second half of this R37, we will carry out confirmatory and follow-up studies of these AD candidate genes. First, SNPs exhibiting family-basedassociation with AD will be confirmed by manual genotyping. Second, they will be confirmed in additional AD family-based samples. Third, tagging SNPs for all inkage disequilibrium blocks in confirmed candidate genes will be tested in the NIMH and confirmatory samples. Fourth, bioinformatic analyses and resequencing will be performed to identify potentially pathogenic mutations and gene variants. The strongest candidate genes will then be validated in a wide array of functional analyses to assess the potential pathogenicity of AD-associatedgene variants.
34 Resulting Publications
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1.
2012Xu Wu; Yan Lu; Yuanlin Dong; Guohua Zhang; Yiying Zhang; Zhipeng Xu; Deborah J Culley; Gregory Crosby; Edward R Marcantonio; Rudolph E Tanzi; et al.
The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1β.
Neurobiology of aging 2012;33(7):1364-78. -
2.
2012Sungho Won; Qing Lu; Lars Bertram; Rudolph E Tanzi; Christoph Lange
Human heredity 2012;73(1):35-46. -
3.
2011A Li; C Zhou; J Moore; P Zhang; T H Tsai; H C Lee; D M Romano; M L McKee; D A Schoenfeld; M J Serra; et al.
Current Alzheimer research 2011;8(3):313-22. -
4.
2010Can Zhang; Andrew Browne; Daniel Child; Jason R Divito; Jesse A Stevenson; Rudolph E Tanzi
The Journal of biological chemistry 2010;285(12):8515-26. -
5.
2010Davide Gianni; Airong Li; Giuseppina Tesco; Kenneth M McKay; John Moore; Kunal Raygor; Marcello Rota; Judith K Gwathmey; G William Dec; Thomas Aretz; et al.
Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy.
Circulation 2010;121(10):1216-26. -
6.
2010Vilmantas Giedraitis; Anna Glaser; Timo Sarajärvi; RoseMarie Brundin; Malin Degerman Gunnarsson; Brit-Maren Schjeide; Rudolph E Tanzi; Seppo Helisalmi; Tuula Pirttilä; Lena Kilander; et al.
CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid.
Neuroscience letters 2010;469(2):265-7. -
7.
2010Lars Bertram; Rudolph E Tanzi
Alzheimer disease: New light on an old CLU.
Nature reviews. Neurology 2010;6(1):11-3. -
8.
2010Can Zhang; Andrew Browne; Jason R Divito; Jesse A Stevenson; Donna Romano; Yuanlin Dong; Zhongcong Xie; Rudolph E Tanzi
Amyloid-β production via cleavage of amyloid-β protein precursor is modulated by cell density.
Journal of Alzheimer's disease : JAD 2010;22(2):683-984. -
9.
2009David W Fardo; K David Becker; Lars Bertram; Rudolph E Tanzi; Christoph Lange
European journal of human genetics : EJHG 2009;17(12):1676-82. -
10.
2009Minji Kim; Jaehong Suh; Donna Romano; Mimy H Truong; Kristina Mullin; Basavaraj Hooli; David Norton; Giuseppina Tesco; Kathy Elliott; Steven L Wagner; et al.
Human molecular genetics 2009;18(20):3987-96. -
11.
2009Brit-Maren M Schjeide; Matthew B McQueen; Kristina Mullin; Jason DiVito; Meghan F Hogan; Michele Parkinson; Basavaraj Hooli; Christoph Lange; Deborah Blacker; Rudolph E Tanzi; et al.
Assessment of Alzheimer's disease case-control associations using family-based methods.
Neurogenetics 2009;10(1):19-25. -
12.
2009Brit-Maren M Schjeide; Basavaraj Hooli; Michele Parkinson; Meghan F Hogan; Jason DiVito; Kristina Mullin; Deborah Blacker; Rudolph E Tanzi; Lars Bertram
GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.
Archives of neurology 2009;66(2):250-4. -
13.
2008Lars Bertram; Brit-Maren M Schjeide; Basavaraj Hooli; Kristina Mullin; Mikko Hiltunen; Hilkka Soininen; Martin Ingelsson; Lars Lannfelt; Deborah Blacker; Rudolph E Tanzi
No association between CALHM1 and Alzheimer's disease risk.
Cell 2008;135(6):993-4; author reply 994-6. -
14.
2008Zhongcong Xie; Deborah J Culley; Yuanlin Dong; Guohua Zhang; Bin Zhang; Robert D Moir; Matthew P Frosch; Gregory Crosby; Rudolph E Tanzi
Annals of neurology 2008;64(6):618-27. -
15.
2008Lars Bertram; Rudolph E Tanzi
Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.
Nature reviews. Neuroscience 2008;9(10):768-78. -
16.
2008In Ho Lee; Deborah J Culley; Mark G Baxter; Zhongcong Xie; Rudolph E Tanzi; Gregory Crosby
Spatial memory is intact in aged rats after propofol anesthesia.
Anesthesia and analgesia 2008;107(4):1211-5. -
17.
2008Barbara A J Schaffer; Lars Bertram; Bruce L Miller; Kristina Mullin; Sandra Weintraub; Nancy Johnson; Eileen H Bigio; Marsel Mesulam; Martina Wiedau-Pazos; George R Jackson; et al.
Association of GSK3B with Alzheimer disease and frontotemporal dementia.
Archives of neurology 2008;65(10):1368-74. -
18.
2008Rudolph E Tanzi
Novel therapeutics for Alzheimer's disease.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 2008;5(3):377-80. -
19.
2008Bin Zhang; Yuanlin Dong; Guohua Zhang; Robert D Moir; Weiming Xia; Yun Yue; Ming Tian; Deborah J Culley; Gregory Crosby; Rudolph E Tanzi; et al.
The Journal of biological chemistry 2008;283(18):11866-75. -
20.
2008Guohua Zhang; Yuanlin Dong; Bin Zhang; Fumito Ichinose; Xu Wu; Deborah J Culley; Gregory Crosby; Rudolph E Tanzi; Zhongcong Xie
The Journal of neuroscience : the official journal of the Society for Neuroscience 2008;28(17):4551-60. -
21.
2007Airong Li; Zhongcong Xie; Yuanlin Dong; Kenneth M McKay; Mary L McKee; Rudolph E Tanzi
Human molecular genetics 2007;16(21):2626-39. -
22.
2007Giuseppina Tesco; Young Ho Koh; Eugene L Kang; Andrew N Cameron; Shinjita Das; Miguel Sena-Esteves; Mikko Hiltunen; Shao-Hua Yang; Zhenyu Zhong; Yong Shen; et al.
Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
Neuron 2007;54(5):721-37. -
23.
2007Zhongcong Xie; Yuanlin Dong; Uta Maeda; Weiming Xia; Rudolph E Tanzi
The Journal of biological chemistry 2007;282(7):4318-25. -
24.
2007Zhongcong Xie; Yuanlin Dong; Uta Maeda; Robert D Moir; Weiming Xia; Deborah J Culley; Gregory Crosby; Rudolph E Tanzi
The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27(6):1247-54. -
25.
2006Zhongcong Xie; Yuanlin Dong; Uta Maeda; Robert Moir; Sharon K Inouye; Deborah J Culley; Gregory Crosby; Rudolph E Tanzi
Isoflurane-induced apoptosis: a potential pathogenic link between delirium and dementia.
The journals of gerontology. Series A, Biological sciences and medical sciences 2006;61(12):1300-6. -
26.
2006Deborah J Culley; Rustam Y Yukhananov; Zhongcong Xie; Reddy R Gali; Rudolph E Tanzi; Gregory Crosby
Altered hippocampal gene expression 2 days after general anesthesia in rats.
European journal of pharmacology 2006;549(1-3):71-8. -
27.
2006Deborah Blacker; Simon Lovestone
Genetics and dementia nosology.
Journal of geriatric psychiatry and neurology 2006;19(3):186-91. -
28.
2006Donna M Romano; Yuanlin Dong; Mikko Hiltunen; Rudolph E Tanzi; Zhongcong Xie
Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 2006;13(2):86-92. -
29.
2006Zhongcong Xie; Yuanlin Dong; Uta Maeda; Paul Alfille; Deborah J Culley; Gregory Crosby; Rudolph E Tanzi
Anesthesiology 2006;104(5):988-94. -
30.
2006Zhongcong Xie; Rudolph E Tanzi
Alzheimer's disease and post-operative cognitive dysfunction.
Experimental gerontology 2006;41(4):346-59. -
31.
2005Zhongcong Xie; Donna M Romano; Rudolph E Tanzi
The Journal of biological chemistry 2005;280(15):15413-21. -
32.
2005Zhongcong Xie; Donna M Romano; Rudolph E Tanzi
Journal of molecular neuroscience : MN 2005;25(1):67-77. -
33.
2004Zhongcong Xie; Donna M Romano; Dora M Kovacs; Rudolph E Tanzi
The Journal of biological chemistry 2004;279(33):34130-7. -
34.
2000J D Buxbaum; C Lilliehook; J Y Chan; R C Go; S S Bassett; R E Tanzi; W Wasco; D Blacker
Neuroscience letters 2000;294(3):135-8.
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