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 most recent mega-meta analysis of PD GWA is a large collaborative effort between all groups that have generated GWA data in Caucasian PD subjects. This analysis has revealed approximately 30 loci, and we have completed 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. A second stage of this analysis is undergoing and centers on expanding the current cross sectional cohort and also completing an ongoing genome wide association study in a longitudinal cohort of PD patients to identify risk loci for progression, response to treatment, and comorbidities.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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Blauwendraat, Cornelis; Faghri, Faraz; Pihlstrom, Lasse et al. (2017) NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases. Neurobiol Aging 57:247.e9-247.e13
Noyce, Alastair J; Kia, Demis A; Hemani, Gibran et al. (2017) Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study. PLoS Med 14:e1002314
Hammer, Monia B; Ding, Jinhui; Mochel, Fanny et al. (2017) SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families. Neurodegener Dis 17:208-212
Blauwendraat, Cornelis; Nalls, Mike A; Federoff, Monica et al. (2017) ADORA1 mutations are not a common cause of Parkinson's disease and dementia with Lewy bodies. Mov Disord 32:298-299
Larsson, Susanna C; Singleton, Andrew B; Nalls, Mike A et al. (2017) No clear support for a role for vitamin D in Parkinson's disease: A Mendelian randomization study. Mov Disord 32:1249-1252
Hayete, Boris; Wuest, Diane; Laramie, Jason et al. (2017) A Bayesian mathematical model of motor and cognitive outcomes in Parkinson's disease. PLoS One 12:e0178982
Siitonen, Ari; Nalls, Michael A; Hernández, Dena et al. (2017) Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study. Neurobiol Aging 53:195.e7-195.e10
Kang, Ju-Hee; Mollenhauer, Brit; Coffey, Christopher S et al. (2016) CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study. Acta Neuropathol 131:935-49
Mehta, Shyamal H; Dickson, Dennis W; Morgan, John C et al. (2016) Juvenile onset Parkinsonism with ""pure nigral"" degeneration and POLG1 mutation. Parkinsonism Relat Disord 30:83-5
Boeve, Bradley F; Dickson, Dennis W; Duda, John E et al. (2016) Arguing against the proposed definition changes of PD. Mov Disord 31:1619-1622

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