The genetic contribution to a number of neurological disorders is thought to be complex in nature, disease risk being driven by a combination of risk alleles commonly present in the human genome. Recently the completion of stages I and II of the international Haplotype Map project and the availability of high-plex SNP assays has made genome wide assay of common genetic variability a realistic endeavor. We have applied genome wide association analysis using 500,000SNPs to a Parkinsons disease cohort from the NIH funded neurogenetics repository. We have combined the data from this work with collaborators from Germany, the US, the UK and Japan. This work has lead to the identification of common variability in SNCA and MAPT as unequivocal risk factors for Parkinson's disease. We have now extended this work and combined results with other large genotyping projects in PD and related diseases to identify additional risk loci for this disease, identifying an additional 15 risk loci for Parkinson's disease. This work showed for the first time unequivocal evidence that the genetic basis of Parkinson's disease is complex and substantive. Not only has this effort revealed a greater than previously thought genetic component, but it has also nominated a host of new targets with which to understand the biological basis of Parkinson's disease. Our current effort revolves around a mega-meta analysis of PD GWA, that is a large collaborative effort between all groups that have generated GWA data in Caucasian PD subjects. This analysis revealed approximately 30 loci, and we are currently working on replication of these in an independent series. The next component of this work involves large scale resequencing to find biologically relevant variants that mediate the common risk and in addition are responsible as rare causal mutations. We are currently preparing a manuscript for submission that reports the identification and replication of 28 independent risk loci for Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000949-08
Application #
8736663
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2013
Total Cost
$689,950
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Nalls, Mike A; Bras, Jose; Hernandez, Dena G et al. (2015) NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases. Neurobiol Aging 36:1605.e7-12
Ghani, Mahdi; Lang, Anthony E; Zinman, Lorne et al. (2015) Mutation analysis of patients with neurodegenerative disorders using NeuroX array. Neurobiol Aging 36:545.e9-14
Dong, Jing; Gao, Jianjun; Nalls, Michael et al. (2014) Susceptibility loci for pigmentation and melanoma in relation to Parkinson's disease. Neurobiol Aging 35:1512.e5-10
Nalls, Mike A; Pankratz, Nathan; Lill, Christina M et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 46:989-93
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Paisan-Ruiz, Coro; Washecka, Nicole; Nath, Priti et al. (2009) Parkinson's disease and low frequency alleles found together throughout LRRK2. Ann Hum Genet 73:391-403
Singleton, Andrew; Morris, Huw (2008) Association, expression, pathobiology: is too much tau in PD a blueprint for genetic association? Neurology 71:11-2

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