The Morris K. Udall Center of Excellence for Parkinson’s Disease Research at the University of Miami

Director: Jeffery M. Vance, M.D., Ph.D.

Title: The Genetics of Parkinsonism

Website: http://udall.med.miami.edu/

Central Theme

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.   

Center Structure

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).

Recent Significant Advances

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.   

Available Resources

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.

Collaborations with other Udall Centers

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.  

Plans for the Coming Year

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.

Selected Recent Publications

1. Nuytemans K, et al.   C9ORF72 repeat expansion is a risk factor for Parkinson Disease. The 62nd Annual Meeting of the American Society of Human Genetics (ASHG), San Francisco, CA, November 6-10, 2012 (Platform presentation).  Intermediate size repeats for the same repeat that is causal in ALS and FTD is a risk factor for PD. These are rare variants that are not seen easily by sequencing
2. Lill CM, et al.  Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database. PLoS Genetics. 2012 Mar;8(3):e1002548. Epub 2012 Mar 15.
   Pankratz N, Beecham GW, et al.  PD GWAS Consortium. Meta-analysis of Parkinson disease: Identification of a novel locus, RIT2. Ann Neurol. 2012 Mar;71(3):370-84. doi: 10.1002/ana.22687. PMC3354734.  Confirming the gene (RIT2) originally seen in our Udall dataset as a risk factor for PD
3. Martins M et al.  Convergence of microRNA expression profiling, α-synuclein interacton and GWAS results support the role of the glycosphingolipid biosynthesis and the ubiquitin proteasome system in Parkinson’s disease. PLoS One. 2011;6(10):e25443. PMC3189215.  Senior author Dr. Oliveira is a former fellow of our Udall center and now a successful researcher PD in Lisbon, Portugal
4. Butler et al.  Vitamin D Receptor Gene as a Candidate Gene for Parkinson Disease, Ann Hum Genet 2011;75(2):201-210.  The most significant single nucleotide polymorphism (SNP) in our study was at the 3’ end of the gene, and it has also been associated with both Multiple Sclerosis and Alzheimer disease risk.  This finding correlates well with the multiple recent reports that low Vitamin D concentrations are associated with increased risk for PD, as the VDR receptor is its primary mediator of Vitamin D’s function, and was part of the motivation for the project III GWAIS study
5. Hamza et al., PloS Genet 2011; 7(8):e1002237.  Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson’s Disease Modifier Gene via Interaction with Coffee .  A collaborative study looking at genes that could explain the beneficial effect of coffee for PD
6. Edwards et al., PloS One 2011;6(2):e16917.  Pathway Analysis:  Identifying Consensus Disease Pathways in Parkinson’s Disease using an Integrative Systems Biology Approach.  We have performed pathway analysis in both GWAS and expression data from brain tissue and converged them to identify common pathways that are important to developing PD.  Four of the top seven pathways are common to both data sets.  These results support the use of pathway approaches to understanding the genetic factors influencing PD; this approach will be used in evaluation of exome sequencing results in project I and GWAIS results in project III
7. Hamza TH, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nature Genetics. 2010 Sep; 42 (9) :781-5
8. Hedges DJ, et al.  “Comparison of three targeted enrichment strategies on the SOLiD sequencing platform” PloS One 2011;6(4)e18593. Used Udall PD samples in analysis of approaches
9. Alcalay RN et al.  Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study.  Neurology. 2011 Jan 25;76(4):319-26
10. Caccappolo E, Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study. 2011 Jan;17(1):91-100. PMID: 21092386

Community Outreach and Education

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.  

Public Health Statement

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.