Director: Jeffery M. Vance, M.D., Ph.D.
Title: The Genetics of Parkinsonism
Budget End Date: 8/31/2016
The central theme of the Udall Center at the University of Miami 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” which is focused on the hypothesis that rare genetic variants individually and in aggregate contribute to risk of developing PD. Project II’s specific aims have been modified, and now focus on identifying methylation and gene expression changes in three areas of the brain affected by PD. Project III, “Vitamin D concentration, genetic modifiers, and PD” tests the hypothesis that the association between low plasma Vitamin D concentrations and PD might be modified by genetic factors. The cores are an administrative core and three scientific resource cores: Clinical Resources Core, the Statistical Analysis and Bioinformatics core and the Disease Modeling Core.
Project I: We have finished Whole Exome Sequencing (WES) on 500 cases and 500 controls and identified initial rare variants (RV) of interest. We have just completed a replication dataset of 500 individuals sequenced for the top 300 genes with significant gene-based association from the initial WES analysis. In addition we have sequenced the genomic region of PARK10 defined by the recent association study in autopsy-confirmed PD and controls. We have narrowed a region with a significant LOD score for PD in our Amish data. Using preliminary data from project 1, we have successfully obtained a grant from the Department of Defense to create a database for PD of rare variants and mutations. This project addresses the NINDS PD2014 conference Basic Research Recommendation #7, “Develop a more detailed understanding of the genetic basis of PD."
Project II: The original Specific Aim 1 for this project was incorporated into another, collaborative project of the NINDS Parkinson’s Disease Biomarkers Program (PDBP), necessitating redesign of the Specific Aims. The Project has identified 20 PD cases and 20 controls with autopsy material for RNA and DNA extraction for methylation and RNA sequencing studies. This project addresses the following research priorities identified at the NINDS PD2014 conference:
Project III: In the largest study to date, we have shown that both vitamin D (vit D) deficiency (total vit D<20ng/mL) and vit D insufficiency (total vit D<30ng/mL) are strongly associated (P<0.0001) with PD risk. Low levels of vit D from different sources, i.e. vit D2 (only from diet and supplements) and vit D3 (mainly from sunlight exposure), are both significantly associated with PD risk. This strongly suggests that risk of low vit D levels and PD is not simply due to lack of sunlight exposure in individuals with PD and impaired mobility, but acts as a true risk factor. This finding was presented as a platform talk at the 2013 American Society for Human Genetics (ASHG) meeting. This aim addresses several research recommendations from the NINDS PD2014 conference, including
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 have collected 112 brains through our autopsy program, of which at least 63 had autopsy-confirmed PD, 13 PSP, 5 MSA and 3 CBD. We have DNA and plasma samples on 1660 individuals from 335 multiplex families and 2131 individuals from 935 singleton families (RNA on some samples). We have collected blood from 10 PD cases for induced pluripotent stem (iPS) cell formation. We have created multiple iPS cell lines following NINDS guidelines. Yeast constructs with EIF4G1 known mutations have been developed as well. Those interested in collaborations should contact Dr. Vance. The Autopsy-Confirmed PD GWAS Consortium (ACPDGC) data is available through the NIH database of Genotypes and Phenotypes, dbGAP (phs00394.v1.p1). WES data on cases and controls approved by the University of Miami IRB is currently being added to dbGAP.
Center investigators will continue the research on all three projects. We are focusing our modeling core on iPS cells exclusively, working on research findings from all three projects. These studies address NINDS PD2014 Translational Research Recommendation #3, “Develop resources ... include well–characterized replications sets of iPS cell lines from sporadic, dominant and recessive PD cases.”
The Miami Udall Center will also organize a second autopsy-confirmed dataset for replication studies, which addresses NINDS PD2014 Clinical Research Recommendation #3, “Characterize the long-term progression of PD and understand the mechanisms that underlie its heterogeneity in clinical presentation and rates of progression.to disease… may include clusters of clinical features as well as biological factors such as genotype and biomarkers.”
The Miami Udall Center has sponsored and received funding for a five year NINDS R25 grant entitled “Summer Research Experience in biological and computational Sciences”. This will expand the existing JJ Vance Summer Internships run by the Hussman Institute for Human Genomics. During the summer of 2014, three high school students worked with Udall Center investigators in this program. 76% of the past JJ Vance interns have minority ethnic backgrounds, and 80% are pursuing STEM majors in college. The Udall Center continues to train postdoctoral fellows, as well as provide support for a PhD graduate student working in induced pluripotent stem (iPS) cell studies in PD. The Miami Udall Center made 5 presentations to outside groups this year.
The Udall Center at the University of Miami 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 fourteen 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 February 10, 2015