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


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

Title: The Genetics of Parkinsonism

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

Budget End Date: 8/31/2016

Central Theme

The central theme of the Udall Center at the University of Miami is the identification of the genes and complex biological mechanisms leading to the development of the common forms of Parkinson disease (PD).

Center Structure

The Miami Udall Center consists of three projects and four cores, all highly interactive. Project I, “Identification of rare variants in PD through whole exome sequencing” is focused on the hypothesis that rare genetic variants individually and in aggregate contribute to risk of developing PD. We now understand that as a group, rarer genetic changes (<5% in the population) are the most common group of genetic variants seen in our genomes.   Project II, “Epigenetic studies in PD,” focuses on identifying methylation and gene expression changes in three areas of the brain affected by PD, representing early, clinical onset and later regions in the progression of 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 include an Administrative Core and three scientific resource cores: Clinical Resources, Statistical Analysis and Bioinformatics, and Disease Modeling.

Recent Significant Advances

Project I: Identification of rare variants in PD through whole exome sequencing. 

Initial analysis of Whole Exome Sequencing (WES) on almost 1000 cases and 400 controls has been completed.  We have identified multiple rare variants of interest, many of which overlap other known neurodegenerative diseases.  We are now using inducible pluripotent stem cell derived neurons from the Disease Modeling Core to model these and other genetically identified changes for possible functional effects.   In addition, we led a 14 center consortium that published evidence demonstrating that the PARK10 locus is one of the strongest associations known to date for “idiopathic” PD, using autopsy-proven cases and controls.  This study demonstrated conclusively the extensive pathological and genetic heterogeneity of clinical PD.  We have performed a comparative genomic hybridization on PD cases and are examining the data to look for copy number variations that could contribute to PD.  Over 60 members of Amish families with PD have been whole genome sequenced and we will be examining this data in this coming year.  

Project Goals aligned with NINDS PD2014 Research Priorities

Project I addresses the NINDS PD2014 research priority Basic Research Recommendation 7, “Develop a more detailed understanding of the genetic basis of PD."

Project II: Epigenetic studies in PD. 

This project examines epigenetic influences in PD, specifically methylation.  We have completed our initial global methylation studies in three brain regions affected at different stages of PD, including the Dorsal Motor Nucleus (early), Substantia Nigra (clinical onset) cingulate gyrus (late) as well as transcriptome studies (RNA sequencing).  A replication set of samples in now under analysis.

Project Goals aligned with NINDS PD2014 Research Priorities

Project II addresses the following NINDS PD2014 Research Priorities:

Clinical Research Recommendation 1, “define …events that underlie phenoconversion to clinical PD.”,
Translational Research Recommendation 4, “develop an integrated PD knowledge database (epigenetic status, sequencing, RNA) and
Translational Research Recommendation 8, “develop a thorough understanding of targets and pathways associated with pathogenesis and pathophysiological mechanisms of PD with emphasis on those validated by human genetics.”

Project III: Vitamin D concentration, genetic modifiers, and PD. 

We have recently published data (Wang et al 2015) demonstrating 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. We have now measured Vitamin D levels on samples from two independent, large genotyped databases and identified several gene interactions with vit D, currently under further study.    
 

Project Goals aligned with NINDS PD2014 Research Priorities

Project III addresses several NINDS PD2014 Research Priorities including:
Clinical Research Recommendation 1, “define …events that underlie phenoconversion to clinical PD”,
Clinical Research Recommendation 6, “determine factors that facilitate public health interventions…and ”
Translational Research Recommendation 8, “develop a thorough understanding of targets and pathways associated with pathogenesis and pathophysiological mechanisms of PD with emphasis on those validated by human genetics.”

Resources Available

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, which includes at present 66 autopsy-confirmed PD, 14 PSP, 5 MSA, 3 CBD, 8 Alzheimer and 8 controls. 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 25 iPSC PD and control lines currently being studied. 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 for VPS35 and EIF4G1 has been placed in dbGAP.  Whole exome sequencing data on the same individuals will be available soon.    

Plans for the Coming Year

Center investigators will continue the research on all three projects, and look to expand functional, epigenetic and transcriptome studies that are underway.  

Select Recent Publications

Wang L, Evatt ML, Maldonado LG, Perry WR, Ritchie JC, Beecham GW, Martin ER, Haines JL, Pericak-Vance MA, Vance JM, Scott WK. Vitamin D from different sources is inversely associated with Parkinson disease. Mov Disord. 2015 Apr;30(4):560-6. PMCID: PMC4390412

Beecham GW, Dickson DW,  Scott WK, Martin E R, Schellenberg G, on behalf of the Alzheimer Disease Genetics Consortium, Nuytemans K, Larson EB, Buxbaum JD, Trojanowski JQ, Van Deerlin VM, Hurtig HI, Mash DC, Beach TG,  Troncoso J C,  Pletnikova O, Frosch MP, Ghetti B, Foroud TM, Honig LS, Marder K, Vonsattel J P, Goldman SM, Vinters HV, Ross OA, Wszolek ZK, Wang L, Dykxhoorn DM, Pericak-Vance MA, Montine TJ, Leverenz JB, Dawson TM,  Vance JM.  The PARK 10 locus is a major locus for sporadic, neuropathologically-confirmed Parkinson disease. Neurology. 2015 Mar 10;84(10):972-80.  PMCID: PMC4352096 [Available on 2016-03-10]

Nalls MA, Bras J, Hernandez DG, Keller MF, Majounie E, Renton AE, Saad M, Jansen I, Guerreiro R, Lubbe S, Plagnol V, Gibbs JR, Schulte C, Pankratz N, Sutherland M, Bertram L, Lill CM, DeStefano AL, Faroud T, Eriksson N, Tung JY, Edsall C, Nichols N, Brooks J, Arepalli S, Pliner H, Letson C, Heutink P, Martinez M, Gasser T, Traynor BJ, Wood N, Hardy J, Singleton AB; International Parkinson’s Disease Genomics Consortium (IPDGC); Parkinson’s Disease meta-analysis consortium(Collaborator, VANCE JM). NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases. Neurobiol Aging. 2015 Mar;36(3):1605.e7-12. PMCID: PMC4317375

Additional Accomplishments

The Miami Udall Center has been the anchor for three successful grants.  The first is an R25 (1R25NS090624) to bring rising high school seniors directly into active research in the laboratories of the John P. Hussman Center of Human Genomics, where the Miami Udall is located.  Over 130 applicants from greater than 60 high schools in Miami and Broward counties applied this year, with 16 students chosen.  Approximately 75% of the students are self-identified as minorities.  The second grant is a Department of Defense grant, W81XWH-14-1-0097 to create a new PD database with rare variants ranked by likely importance to PD.  This database has been populated and will come online this year.  Finally, a National Parkinson Foundation grant has been secured to facilitate the inclusion of Hispanic/Latino PD patients into research studies.   

Public Health Statement

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 fifteen 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 Modified February 7, 2016