Director: Jeffery M. Vance, M.D., Ph.D.
Title: The Genetics of Parkinsonism
The central theme of the Udall Center at the University of Miami (UM) is the identification of the genes and complex mechanisms leading to the development of Parkinson disease (PD). These discoveries may then be translated into tools for early detection of increased risk for disease, leading to early intervention, and provide therapeutic targets for PD.
The center consists of three projects and four cores. The projects are: Project I, “Identification of rare variants in PD through whole exome sequencing” (Dr. Jeffery Vance, PI), which focuses on the on the hypothesis that rare genetic variants individually and in aggregate contribute to risk of developing PD. Project II is entitled “Long non-coding RNAs as epigenomic modulators and cerebrospinal fluid (CSF) biomarkers in PD” (Drs. Mohammad Faghihi and Claes Wahlestedt, PIs)and examines the hypothesis that non-coding RNAs are deeply involved in PD, contribute to risk of PD and can be measured in CSF as an early biomarker for disease. Project III, “Vitamin D concentration, genetic modifiers, and PD” (Drs. William Scott and Liyong Wang, PIs) tests the hypothesis that the association between low plasma Vitamin D (vit D) concentrations and PD might be modified by genetic factors. The cores are an Administrative core (headed by the center director, Jeffery M. Vance, MD, PhD), and three scientific resource cores: the Clinical Resources core (Dr. Bill Scott, director), the Statistical Analysis and Bioinformatics core (Dr. Gary Beecham, director) and the Disease Modeling core (Dr. Derek Dykxhoorn, director).
Project I: We have performed whole exome sequencing on close to 300 individuals with PD out of a planned 500 patients and a similar number of controls. Initial analyses have identified many rare variants that are currently undergoing validation. We have also identified that the recent repeat in C9ORF72 is a risk factor for PD.
Project II: We are currently collaborating with the Pacific Northwest Udall Center (PANUC) at the University of Washington on this project, sharing CSF samples. Over 60 CSF samples (30 PD, 30 controls) have had their CSF RNA sequenced by September 2012. We are currently performing whole exome sequencing on these same 60 individuals in Project I.
Genome wide association study (GWAS) on autopsy proven PD, with minimal Alzheimer findings: This study, supported by supplemental funding from the NINDS, with the Miami Udall Center as the coordinating site of the Autopsy-confirmed PD GWAS Consortium (APDGC), which genotyped DNA samples on 543 individuals with autopsy-confirmed PD and 317 controls with no significant neuropathology for GWAS genotyping at the NIH Center for Inherited Disease Research (CIDR). These data have been combined with GWAS genotypes from 624 additional neuropathologically normal controls from the Alzheimer Disease Genetics Consortium (ADGC), for a total of 941 neuropathologically normal controls for analysis. The hypothesis tested by this project is that prior GWAS studies with clinically-diagnosed cases and controls may have failed to detect some genetic factors due to diagnostic heterogeneity in the cases or controls. It is estimated that 10-25% of cases diagnosed clinically with PD may have other diagnoses upon autopsy. Studying autopsy-confirmed cases and controls may reduce error and improve statistical power to detect additional genetic factors. The resulting dataset, which will be made publicly available through the NIH Database of Genotypes and Phenotypes (dbGaP), will be a great resource for all PD researchers in the future. This consortium includes 11 centers, including participants from six institutions with Udall Centers (University of Pennsylvania, University of Washington, Mayo Clinic Jacksonville, Johns Hopkins University, Columbia University, University of Miami). Genotyping and initial data analysis have been completed, and the manuscript describing these results is currently under preparation.
The Miami Udall Center maintains a large DNA and brain tissue repository with samples obtained from clinically well-characterized individuals for genetic and neuropathologic studies. We also have created several induced pluripotent stem cell (IPSC) lines. The autopsy GWAS data will be available through dbGAP. Autopsy material on PD and Parkinsonism is available. Those interested in collaborations should contact Dr. Vance.
Currently Projects I and II have an active collaboration with the University of Washington Udall center on biomarker and sequencing studies. The autopsy GWAS supplement has collaborations with six Udall Centers (see above). Project III is collaborating with neurologists at Emory on Vitamin D analyses in PD.
Research on all three projects will continue. The clinical resources core will continue to conduct follow-up visits of participants in the brain tissue donation program.
Two National Parkinson Foundation Disease chapters in Florida visited the Udall center for presentations and tours, as well as one chapter from the Middle East. The Udall center is funding a PhD. graduate student working in iPSC studies in PD.
The Miami Udall Center seeks to identify genetic factors related to PD and determine how they interact with each other and the environment to influence and contribute to the development of PD. Over the past thirteen years, investigators from the Miami Udall Center have identified forms of many genes that increase or decrease the risk of developing PD. Each of these discoveries enhances the developing picture of the biology underlying PD and suggests avenues for further study.
Last updated March 20, 2013