Project I - Genetic studies in Parkinson Disease (PD) have been a major tool fueling the tremendous growth in research. However, there is increasing realization that common variations (MAF >5%) alone are not responsible for the genetic contribution to risk for developing PD and many other complex disorders. One of the alternative hypothesis for this missing genetic contribution are rare variants. Over the past year we initiated one of the first whole exome sequencing (WES) projects for Parkinson disease to search for rare variants contributing to PD. This project continues this work, incorporates our recent work on pathways into our analyses, and will provide information on the pathways and function of the genes discovered.
Specific Aim 1 identifies an initial set of rare variants and additional SNPs in a discovery set of 500 Parkinson Disease patients and 500 controls for testing in our replication dataset in Specific Aim 3a.
Specific Aim 2 utilizes a large Amish pedigree to look for rare variants using WES, targeted capture and potentially whole genome sequencing. The Amish present a group of individuals with both a relatively uniform environmental exposure history and increased genetic homogeneity. Linkage analysis reveals a strong locus on chromosome 9 In several branches of the pedigree, and additional loci on other chromosomes. This is thus a good model for PD in the outbred population.
In Specific Aim 3 we will test the top 200 genes and/or variants from our discovery dataset in an additional 500 cases and 500 controls . To accomplish this efficiently we will create a targeted capture for next generation sequencing . Analyses of this verification datasets will include multiple subsets of the data including by variant, variants within a gene "cluster", pathway analyses, gene networks of interest such as mitochondrial nuclear genes and AAO differences. In order to improve information on pathways and also evaluate the identified genes and there relationship to other known PD genes, we will examine differentially expression using silencing and other interventional techniques for the candidate genes in three different biological systems through Core D: yeast, zebrafish and induced pluripotent stem cells derived from PD patients and controls.
|Rawlik, Konrad; Rowlatt, Amy; Tenesa, Albert (2016) Imputation of DNA Methylation Levels in the Brain Implicates a Risk Factor for Parkinson's Disease. Genetics 204:771-781|
|Lubbe, Steven J; Escott-Price, Valentina; Brice, Alexis et al. (2016) Is the MC1R variant p.R160W associated with Parkinson's? Ann Neurol 79:159-61|
|Nuytemans, Karen; Maldonado, Lizmarie; Ali, Aleena et al. (2016) Overlap between Parkinson disease and Alzheimer disease in ABCA7 functional variants. Neurol Genet 2:e44|
|El Hokayem, Jimmy; Cukier, Holly N; Dykxhoorn, Derek M (2016) Blood Derived Induced Pluripotent Stem Cells (iPSCs): Benefits, Challenges and the Road Ahead. J Alzheimers Dis Parkinsonism 6:|
|Esanov, Rustam; Belle, Kinsley C; van Blitterswijk, Marka et al. (2016) C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. Exp Neurol 277:171-7|
|Lubbe, S J; Escott-Price, V; Brice, A et al. (2016) Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease. Neurobiol Aging 48:222.e1-222.e7|
|Hossein-Nezhad, Arash; Fatemi, Roya Pedram; Ahmad, Rili et al. (2016) Transcriptomic Profiling of Extracellular RNAs Present in Cerebrospinal Fluid Identifies Differentially Expressed Transcripts in Parkinson's Disease. J Parkinsons Dis 6:109-17|
|Xiong, Nian; Li, Nuomin; Martin, Eden et al. (2016) hVMAT2: A Target of Individualized Medication for Parkinson's Disease. Neurotherapeutics 13:623-34|
|Zeier, Zane; Esanov, Rustam; Belle, Kinsley C et al. (2015) Bromodomain inhibitors regulate the C9ORF72 locus in ALS. Exp Neurol 271:241-50|
|Pastori, Chiara; Kapranov, Philipp; Penas, Clara et al. (2015) The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. Proc Natl Acad Sci U S A 112:8326-31|
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