This proposal seeks to discover a new gene(s) within a candidate region on chromosome 1p that modifies PD susceptibility and/or age at onset. The characterization of such a gene, and the pathways in which it participates, will further our understanding of the molecular events that lead to selective neurodegeneration in PD. This knowledge might serve to identify novel therapeutic targets which could be used to prevent and better treat the disease.

Public Health Relevance

Parkinson's disease (PD) affects 1-2% of the population over 60 years of age and thus constitutes a major problem in public health. Current treatment strategies are only palliative and a better understanding of the molecular mechanisms underlying PD is necessary in order to develop more definitive neuroprotective therapies. Human genetic studies are a valuable tool in this endeavor. A new candidate region for PD was recently identified on chromosome 1p in two independent linkage studies. However, the identity of the disease gene(s) within this region has not yet been determined. In this application, we propose to fine-map the candidate interval using 7,600 single nucleotide polymorphisms (SNPs) in 300 multiplex PD families recruited from across the United States. FBAT- based methods will be utilized to identify SNPs which modify PD risk or age at onset. Exploratory analyses will be undertaken to test for gene x environment interactions. We will then validate markers which meet a pre-defined significance threshold in an independent case control sample of 2,000 subjects. Finally, an extensive bioinformatics analysis will be performed to assemble a list of putative functional risk variants which will subsequently be tested for effects on gene expression and/or protein function via in vitro assays. This work has the potential to discover a new disease gene(s) which could provide important insights into the pathogenesis of PD that ultimately translate into improved strategies for diagnosis, prevention, and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065070-04
Application #
8289645
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Sutherland, Margaret L
Project Start
2009-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$496,296
Indirect Cost
$102,410
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wang, Liyong; Maldonado, Lizmarie; Beecham, Gary W et al. (2016) DNA variants in CACNA1C modify Parkinson disease risk only when vitamin D level is deficient. Neurol Genet 2:e72
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102
Mata, Ignacio F; Davis, Marie Y; Lopez, Alexis N et al. (2016) The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot. Am J Med Genet B Neuropsychiatr Genet 171:925-30
Costa-Mallen, Paola; Zabetian, Cyrus P; Hu, Shu-Ching et al. (2016) Smoking and haptoglobin phenotype modulate serum ferritin and haptoglobin levels in Parkinson disease. J Neural Transm (Vienna) 123:1319-1330
Cholerton, Brenna; Larson, Eric B; Quinn, Joseph F et al. (2016) Precision Medicine: Clarity for the Complexity of Dementia. Am J Pathol 186:500-6
Davis, Marie Y; Johnson, Catherine O; Leverenz, James B et al. (2016) Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 73:1217-1224
Costa-Mallen, Paola; Zabetian, Cyrus P; Agarwal, Pinky et al. (2016) Response to the letter ""Haptoglobin phenotype and Parkinson disease risk"" by Delanghe et al. Parkinsonism Relat Disord 22:110-1
Shi, Min; Kovac, Andrej; Korff, Ane et al. (2016) CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. Alzheimers Dement 12:1125-1131
Stewart, Tessandra; Sossi, Vesna; Aasly, Jan O et al. (2015) Phosphorylated α-synuclein in Parkinson's disease: correlation depends on disease severity. Acta Neuropathol Commun 3:7
Mata, Ignacio F; Jang, Yongwoo; Kim, Chun-Hyung et al. (2015) The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. Mol Neurodegener 10:50

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