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 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 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.
The center consists of three research 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 is entitled “Long non-coding RNAs as epigenomic modulators and cerebrospinal fluid (CSF) biomarkers in PD” and examines the hypothesis that epigenetics is involved in PD. It involves looking at CSF and brain tissue for these changes. 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: By the end of 2013 we will have performed whole exome sequencing on close to 500 individuals with PD and 200 controls. From this work we have published evaluation of EIF4G1 and VPS35 variants for PD. Initial analyses have identified many rare variants in PD. These will need replication in a second dataset to see which ones are truly important in PD. We have also identified that intermediate size repeats of C9ORF72 are a risk factor for PD (Nuytemans et al, 2013).
Project II: CSF samples (30 PD, 27 controls) have had their CSF RNA sequenced and are in initial analysis.
Project III: The largest to-date measurement of Vitamin D levels in PD patients and controls has been measured using Mass Spectrometry. Initial GWAS studies looking at interaction with Vitamin D levels has been performed, and work is ongoing on replication of the initial findings.
Research continues on all three projects. We are modeling effects of the R1205H EIF4G1 variant that has a high incidence of PD. The Clinical Resources Core will continue to conduct follow-up visits of participants in the brain tissue donation program. We will also organize a second dataset to replicate our initial novel findings in the GWAS autopsy study.
Currently we have active collaborations with 30 different groups working on 13 different research activities in PD. These include active collaborations with five different Udall centers.
The largest collaboration is the “Genome Wide Association Study (GWAS) on Autopsy confirmed Parkinson cases and normal controls”. Our Udall center is the organizing and primary analysis center for the first GWAS in PD using autopsy confirmed controls and cases. The consortium involves 19 different groups and also includes samples from the Alzheimer’s Disease Research Consortium.
The Autopsy-Confirmed PD GWAS Consortium (APDGC) data is available through the NIH Database of Genotypes and Phenotypes (dbGaP, Study Accession phs000394.v1.p1)
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 57 PD brains through our autopsy program, out of 107 total brains collected. We also have created several iPSC lines. Those interested in collaborations should contact Dr. Vance.
The Miami Udall Center hosted two different National Parkinson Foundation (NPF) chapters to a visit of the Udall center and the Hussman Institute. Center faculty also traveled to local NPF meetings to give talks on research ongoing in our Udall Center.
The Miami Udall Center is training the next generation of PD researchers through support of a PhD graduate student working in induced pluripotent stem cell (iPSC) cell studies in PD, as well as several postdoctoral fellows. Two high school students (JJ Vance Foundation Fellows) worked in the Udall Center in the summer of 2013.
C9ORF72 Intermediate Repeat Copies Are a Significant Risk Factor for Parkinson Disease. Nuytemans K, Bademci G, Kohli MM, Beecham GW, Wang L, Young JI, Nahab F, Martin ER, Gilbert JR, Benatar M, Haines JL, Scott WK, Züchner S, Pericak-Vance MA, Vance JM. Ann Hum Genet. 2013 Jul 12. PMID: 23845100
High-resolution survey in familial Parkinson disease genes reveals multiple independent copy number variation events in PARK2. Wang L, Nuytemans K, Bademci G, Jauregui C, Martin ER, Scott WK, Vance JM, Zuchner S. Hum Mutat. 2013 Aug; 34(8):1071-4. PMID: 23616242
Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease.
Nuytemans K, Bademci G, Inchausti V, Dressen A, Kinnamon DD, Mehta A, Wang L, Züchner S, Beecham GW, Martin ER, Scott WK, Vance JM. Neurology. 2013 Mar 12; 80(11):982-9. PMID: 23408866
Last updated November 6, 2013