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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000951-07
Application #
7732372
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2008
Total Cost
$161,081
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74
Kun-Rodrigues, Celia; Ross, Owen A; Orme, Tatiana et al. (2017) Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies. Neurobiol Aging 49:214.e13-214.e15
Guerreiro, Rita; Escott-Price, Valentina; Darwent, Lee et al. (2016) Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging 38:214.e7-214.e10
Sassi, Celeste; Capozzo, Rosa; Gibbs, Raphael et al. (2016) A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy. J Alzheimers Dis 53:475-85
Tranah, Gregory J; Yokoyama, Jennifer S; Katzman, Shana M et al. (2014) Mitochondrial DNA sequence associations with dementia and amyloid-? in elderly African Americans. Neurobiol Aging 35:442.e1-8
Federoff, Monica; Jimenez-Rolando, Belen; Nalls, Michael A et al. (2012) A large study reveals no association between APOE and Parkinson's disease. Neurobiol Dis 46:389-92
Tranah, Gregory J; Nalls, Michael A; Katzman, Shana M et al. (2012) Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly. J Alzheimers Dis 32:357-72
Pearson, Justin P; Williams, Nigel M; Majounie, Elisa et al. (2011) Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. J Neurol 258:647-55
Guerreiro, Rita Joao; Baquero, Miquel; Blesa, Rafael et al. (2010) Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging 31:725-31
Guerreiro, Rita J; Washecka, Nicole; Hardy, John et al. (2010) A thorough assessment of benign genetic variability in GRN and MAPT. Hum Mutat 31:E1126-40

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