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 and provide therapeutic targets for PD.  

Center Structure

The core structure of the center consists of an administrative core (headed by the center director, Jeffery M. Vance, MD, PhD), and three scientific resource cores.  One is the Clinical Resources core (headed by Dr. William Scott) which collaborates with UM Movement Disorders Division physicians (Drs. Fatta Nahab and Carlos Singer) to follow longitudinally a cohort of individuals with PD, their relatives, and unaffected spouses.  The core also maintains the Miami Udall Center brain bank (in collaboration with the University of Miami Brain Bank, directed by Dr. Deborah Mash).  The Statistical Analysis and Bioinformatics core (headed by Dr. Gary Beecham) provides analytic assistance to all projects and cores and maintains the center databases.  The Disease Modeling core (Dr. Derek Dykxhoorn, director) facilitates the rapid identification of the most appropriate models for examining loss of function of specific genes or non-coding RNAs implicated by the three research projects.  The core maintains expertise in zebrafish, yeast, and induced pluripotent stem cells (iPSCs) for modeling these genetic effects.  

The center supports three research projects which approach the central theme from different perspectives:

Project I, “Identification of rare variants in PD through whole exome sequencing” (Dr. Jeffery Vance, PI) focuses on the on the hypothesis that rare genetic variants individually and in aggregate contribute to risk of developing PD.  To examine this hypothesis we are performing whole exome sequencing on over 500 individuals with PD and 500 controls.  These data will be used to look for genes with clustered rare variants or specific changes that are contributing to PD risk.  These samples include individuals with rapid progression of motor symptoms and others with very slow progression, studied in collaboration with the UCLA to look for modifier genes that contribute to the differences in rates of progression. The eventual goal is to produce a high risk genetic profile that can be used in eventual preventive approaches for PD.  

Project II, “Long non-coding RNAs as epigenomic modulators and cerebrospinal fluid (CSF) biomarkers in PD” (Drs. Claes Wahlestedt and Mohammad Faghihi, PIs) 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.  Using RNA deep sequencing to profile the complete RNA transcriptome of CSF from 20 individuals with PD and 20 controls, we will identify RNAs that are differentially expressed in individuals with PD compared to the controls. Selected candidates from this discovery dataset will subsequently be tested for specificity and sensitivity in larger cohorts (100 per group) of CSF and plasma samples from PD, controls and other parkinsonian diseases. We will then examine 50 brain tissue samples from PD individuals and 50 brain tissue samples from controls (tissues from five Braak stage regions of 10 PD and 10 controls).  Using RNA deep sequencing and methylation array, we will identify the source of RNA leakage into CSF as well as epigenetic signatures (such as methylation marks) that correlate with RNA expression differences. We will examine the CSF and plasma samples for presence and differential expression of the top mRNA, ncRNA, alternative splice variants as well as corresponding protein biomarkers with differences in PD and control groups. The goal of the study is to identify ncRNA biomarkers of PD risk that could be translated into diagnostic tests or potential therapies.

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 project uses a genome-wide association and interaction study (GWAIS) approach in two existing datasets (each with about 600 individuals with PD and 600 controls) to identify genetic factors that influence risk of PD by modulating vit D concentrations or genetic factors that exert their effects only at certain vit D concentrations.   Significant associations will then be replicated in a third population-based case-control data set.  This project is a collaborative effort of investigators at four institutions with Udall Centers (University of Washington, Emory University, UCLA, and University of Miami).

In addition, supported by supplemental funding from the NINDS, the Miami Udall Center is the coordinating site of the Autopsy-confirmed PD GWAS Consortium (APDGC), which has sent DNA samples on 651 individuals with autopsy-confirmed PD and 316 controls with no significant neuropathology for GWAS genotyping at the Center for Inherited Disease Research (CIDR).  These data will be combined with GWAS genotypes from 1368 additional neuropathologically normal controls from the Alzheimer Disease Genetics Consortium (ADGC), for a total of 1684 neuropathologically normal controls, for analysis later this year.  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 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).

Recent Significant Advances

Identifying Consensus Disease Pathways in Parkinson’s Disease using an Integrative Systems Biology Approach (Edwards et al., PloS One 2011;6(2):e16917). 
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.  The top three pathways were axonal guidance, focal adhesion, and calcium signalling, suggesting additional directions for PD research.  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.  

Vitamin D Receptor Gene as a Candidate Gene for Parkinson Disease (Butler et al., Ann Hum Genet 2011;75(2):201-210.
We also recently published a significant association with the Vitamin D receptor (VDR) and PD risk.  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.  

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson’s Disease Modifier Gene via Interaction with Coffee (Hamza et al., PloS Genet 2011; 7(8):e1002237).
We have collaborated with investigators from the NeuroGenomics Research Consortium on this GWAIS of gene-caffeine interactions.  The Miami Udall Center data set was used to replicate an interaction between GRIN2A SNP rs4998386 and caffeine; an inverse association was only detected in heavy coffee drinkers, a result replicated across four datasets.  The GWAIS approach used in this study is similar to that proposed for studies of interaction between genes and vitamin D concentration in project III.  

PD GWAS Meta-Analysis Consortium (Pankratz et al., submitted)
We continue our participation in the PD GWAS Meta-Analysis Consortium (Foroud, T. PI). The initial meta-analysis was performed on 2.5 million genotyped and imputed SNPs in 4,238 cases and 4,239 controls, and 768 of the most significant were selected for replication genotyping in a second data set of 3223 PD cases and 2035 controls. This effort discovered a novel genetic risk factor for PD, which was successfully replicated in the second data set.  This consortium has joined a larger, international “mega-meta analysis” effort organized by NINDS.  The results of this larger meta-analysis will be complete in late 2011.

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.  Collaborations with several Udall Centers (Northwestern, Virginia, Harvard) and other PD researchers have been established that have utilized these resources.  Those interested in collaborations should contact Dr. Vance.

Plans for the Coming Year

This year marks the initiation of two new projects (II and III) focusing on ncRNA and gene-environment interactions.  Continuing our work on project I, we will generate exome sequence data to identify genes with rare variants contributing to risk of PD, progression of motor symptoms, and extremes of age at onset.  The clinical resources core will continue to conduct follow-up visits of participants in the brain tissue donation program.

Selected Recent Publications

Edwards TL, Scott WK Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Züchner S, Konidari I, Wang G, Singer C, Nahab F, Scott B, Stajich JM, Pericak-Vance MA, Haines J, Vance JM, Martin ER. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 2010 74:97-109.

Marder K, Tang M–X, Mejia-Santana H, Rosado L, Louis ED, Comella C, Colcher A, Siderowf A, Jennings D, Nance M, Bressman S, Scott WK, Tanner C, Mickel S, Andrews H, Waters C, Fahn S, Ross B, Cote L, Frucht S, Ford B,  Alcalay RN, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Greg Neils,  Verbitsky M, Kisselev S, Caccoppolo E, Ottman R, Clark LN.  Predictors of Parkin Mutations in Early Onset Parkinson disease: the CORE-PD Study.  Arch Neurol, 2010 67(6):731-38.

Alcalay RN, Mejia-Santana H, Tang M –X, Rakitin BC, Rosado L, Ross B, Verbitsky M , Kisselev S, Louis ED, Comella C, Colcher A, Jennings D, Nance M, Bressman S, Scott WK, Tanner C, Mickel S, Andrews H, Waters C, Fahn S, Cote L, Frucht S, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B , Siderowf A, Ottman R, Clark LN, Marder K MD, Caccappolo E.  Self report of cognitive impairment and Mini-Mental State Exam Performance in PRKN, LRRK2 and GBA carriers with early onset PD. J Clin Exp Neuropsychol, 2010 32(7):775-779.  

Chung CY, Licznerski P, Alavian K, Simeone A, Lin Z, Martin ER, Vance JM, Isacson O. The transcription factor Otx2 determines axonal projections and vulnerability of midbrain dopaminergic neurons and carries age-dependent genetic risk for Parkinson's disease. Brain. 2010 Jul;133(Pt 7):2022-31.

Alcalay RN, Mejia-Santana H, Tang M –X, Rakitin BC, Rosado L, Ross B, Verbitsky M , Kisselev S, Louis ED, Comella C, Colcher A, Jennings D, Nance M, Bressman S, Scott WK, Tanner C, Mickel S, Andrews H, Waters C, Fahn S, Cote L, Frucht S, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B , Siderowf A, Ottman R, Clark LN, Marder K MD, Caccappolo E.  Self report of cognitive impairment and Mini-Mental State Exam Performance in PRKN, LRRK2 and GBA carriers with early onset PD. J Clin Exp Neuropsychol, 2010 Aug;32(7):775-9.

Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay D,  Doheny KF, Paschall J,  Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA; Payami H. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nature Genetics. 2010 Sep; 42 (9) :781-5

Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Ross BM, Verbitsky M, Kisselev S, Louis ED, Comella C, Colcher A, Jennings D, Nance MA, Bressman SB, Scott WK, Tanner C, Mickel S, Andrews H, Waters C, Fahn S, Cote L, Frucht S, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Siderowf A, Ottman R, Marder K, Clark LN. Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. Arch Neurol. 2010 Sep;67(9):1116-22.

Vance JM, Alib S, Bradley WG, Singer C, Di Monte DA. Gene-Environment interactions in Parkinson’s disease and other forms of parkinsonism. Neurotoxicology. 2010 Sep;31(5):598-602.

Bademci G, Edwards TL, Torres AL, Scott WK, Züchner S, Martin ER, Vance JM, Wang L. A Rare Novel Deletion of Tyrosine Hydroxylase Gene in Parkinson Disease. Hum Mutat. 2010 Oct;31(10):E1767-71.

Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grünblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wüllner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR; Global PD Gene Expression (GPEX) Consortium. PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med. 2010 Oct 6;2(52):52ra73.

Alcalay RN, Siderowf A, Ottman R, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Louis E, Ruiz D, Waters C, Fahn S, Cote L, Frucht S, Ford B, Orbe-Reilly M, Ross B, Verbitsky M, Kisselev S, Comella C, Colcher A, Jennings D, Nance M, Bressman S, Scott WK, Tanner C, Mickel S, Rezak M, Novak KE, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Clark LN, Marder K. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study.Neurology. 2011 Jan 25;76(4):319-26.

Edwards Y, Khuri S, Beecham GW, Bademci G, Tekin D, Martin ER, Scott WK, Jiang Z, Mash DC, ffrench-Mullen J, Pericak-Vance MA, Tsinoremas N, Vance JM. Identifying Consensus Disease Pathways in Parkinson’s disease using an Integrative Systems Biology Approach. PLoS One. 2011 Feb 22;6(2):e16917. PMCID: PMC3043094

Butler MW, Burt A, Edwards T, Zuchner S, Scott WK, Martin ER, Vance JM, Wang L. Vitamin D Receptor Gene Confers Genetic Risks for Parkinson Disease. Ann Hum Genet. 2011 Mar;75(2):201-10. doi: 10.1111/j.1469-1809. PMCID: PMC307706.

Hedges DJ, Guettouche T, Yang S, Bademci G, Diaz A, Andersen A, Hulme WF, Linker S, Mehta A, Edwards YJK, Beecham GB, Martin ER, Pericak-Vance MA, Zuchner S, Vance JM, Gilbert JR. “Comparison of three targeted enrichment strategies on the SOLiD sequencing platform” PloS One 2011;6(4)e18593.  

Caccappolo E, Alcalay RN, Mejia-Santana H, Tang MX, Rakitin B, Rosado L, Louis ED, Comella CL, Colcher A, Jennings D, Nance MA, Bressman S, Scott WK, Tanner CM, Mickel SF, Andrews HF, Waters C, Fahn S, Cote LJ, Frucht S, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer RF, Marsh L, Hiner B, Siderowf AD, Ross BM, Verbitsky M, Kisselev S, Ottman R, Clark LN, Marder KS 2011 Jan J Int Neuropsychol Soc. Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study. 2011 Jan;17(1):91-100. PMID: 21092386

Cummings AC, Lee SL, McCauley JL, Jiang L, Crunk A, McFarland LL, Gallins PJ, Fuzzell D, Knebusch C, Jackson CE, Scott WK, Pericak-Vance MA, Haines JL A genome-wide linkage screen in the amish with Parkinson disease points to chromosome 6.  Ann Hum Genet. 2011 May;75(3):351-8. PMID: 21488853
Shehadeh LA, Yu K, Wang L, Guevara A, Singer C, Vance J, Papapetropoulos.  SRRM2, a potential blood biomarker revealing high alternative splicing in Parkinson's disease.  PLoS One. 2010 Feb 8;5(2):e9104. PMID: 20161708.

Hamza TH, Chen H, Hill-Burns EM, Rhodes SL, Montimurro J, Kay DM, Tenesa A, Kusel VI, Sheehan P, Eaaswarkhanth M, Yearout D, Samii A, Roberts JW, Agarwal P, Bordelon Y, Park Y, Wang L, Gao J, Vance JM, Kendler KS, Bacanu S, Scott WK, Ritz B, Nutt J, Factor SA, Zabetian CP, Payami H.  Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson’s disease modifier gene via interaction with coffee.  PLoS Genetics.  2011; 7(8):e1002237.

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 ten 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.  Future directions for the center include applying cutting-edge genomic technologies to more quickly study DNA sequences and gene expression, and studying how these factors can be used to better diagnose and manage symptoms in people with PD.