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://med.miami.edu/udall/x14.xml

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).

 

Center Structure

The core structure of thecenter consists of an administrative core (headed by the center director, Dr. Jeffery M. Vance, MD, PhD), and two scientific resource cores. One is the ascertainment and clinical core (headed by Dr. William Scott), which collaborates with UM Movement Disorders Division physicians (Drs. Fatta Nahab and Carlos Singer) to enroll individuals with PD, their relatives, and unaffected spouses into genetic studies and the brain tissue donation program. The other is the molecular and neuropathology core (headed by Dr. Stephan Zuchner), which runs the core genomics laboratories for the Udall Center (performing genotyping, sequencing, and expression analysis) and maintains the Miami Udall Center brain bank (in collaboration with the University of Miami Brain Bank, directed by Dr. Deborah Mash).

These cores support four scientific projects, each exploring a particular aspect of PD genetics. Project 1, headed by Dr. Eden Martin, examines candidate genes developed through the other projects for association with PD. Other goals of this project are to develop statistical methodologies for candidate gene studies in a mixed family- and unrelated case-control sample and to use these methods to evaluate gene-gene and gene-environment interactions. Project 2, headed by Dr. Gaofeng Wang, looks at gene expression changes associated with PD in tissues from the brain bank, developing high-priority candidate genes for further examination. Project 3, headed by Dr. Vance, seeks to identify why the J and K haplogroups of the mitochondrial genome are protective for Parkinson Disease. Project 4, headed by Dr. Scott, uses association analysis within regions of genetic linkage to identify high-priority candidate genes for study.

 

Recent Significant Advances

Recent work in the Miami Udall Center has produced some notable scientific findings. Following initial reports of association between variants in the FGF20 gene and PD, this association was narrowed further to a pair of markers in the 3’ untranslated region of the gene, one of which disrupts a binding site for micro-RNA (miRNA) molecules. This leads to increased production of FGF20, which in turn increases alpha-synuclein expression. The manuscript describing these results (Wang G., et al., Am J Hum Genet 2008) received the Cotterman award from the American Society for Human Genetics as one of the two best papers published in 2008.

Two other advances resulted from complementary approaches to screening the entire human genome for regions likely to contain genes related to the development of PD. The first was a genome-wide linkage screen of 5,824 single nucleotide polymorphisms (SNPs) in a set of 278 families of European, non-Hispanic descent (Gao X., et al., Am J Hum Genet 2009). This effort identified two regions, on chromosomes 3q25 and 18q11, with strong evidence for linkage to PD in these families. These regions were not previously detected in our original linkage study (Scott et al., JAMA 2001), suggesting that there is substantial heterogeneity in the genetic factors in families with multiple individuals affected by PD. The second effort utilized a genome-wide association (GWAS) approach, examining 491,376 SNPs for association with PD in a set of 604 individuals with PD and 619 unaffected controls (Edwards et al., submitted). These data were combined with two other publically available GWAS data sets for a joint analysis of 1,752 cases and 1,745 controls. This combined analysis identified genome-wide significant associations with SNPs in the SNCA and MAPT genes that encode the alpha-synuclein and tau proteins, confirming their importance as risk factors for PD. Several other biologically plausible candidate genes were identified and are being actively followed-up.

 

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/McLean Hospital) 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

During the coming year, we continue to follow the genetic discoveries highlighted above – in particular, following up the recently completed genome-wide association study to determine if association in additional genes (besides the consensus associations in alpha-synuclein and microtubule-associated protein tau) can be replicated. We have submitted a manuscript confirming association with Vitamin D receptor in PD, which appears to be associated with many neurodegenerative disorders. We have also initiated work on an algorithm which would identify individuals prior to clinical symptoms that would be at high risk of developing PD using genetic, environmental and other biomarkers.

The Miami Udall Center is preparing a revised renewal application for submission in November. The central theme for the Center will move towards examining the effect of rare variants in PD, identifying the genetic contributions of pre-Parkinson diseases and continued work on mitochondrial genetics, and presymptomatic detection.

 

Selected Recent Publications

Gao X, Martin ER, Liu Y, Mayhew G, Vance JM, Scott WK. Genome-wide linkage screen in familial Parkinson disease identifies loci on chromosomes 3 and 18. Am J Hum Genet. 2009 Apr;84(4):499-504.

Hancock DB, Martin ER, Vance JM, Scott WK. Nitric oxide synthase genes and their interactions with environmental factors in Parkinson's disease. Neurogenetics. 2008 Oct;9(4):249-62.

Hancock DB, Martin ER, Mayhew GM, Stajich JM, Jewett R, Stacy MA, Scott BL, Vance JM, Scott WK. Pesticide exposure and risk of Parkinson's disease: a family-based case-control study. BMC Neurol. 2008 Mar 28;8:6.

Wang G, van der Walt JM, Mayhew G, Li YJ, Züchner S, Scott WK, Martin ER, Vance JM. Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet. 2008 Feb;82(2):283-9.

Gao X, Scott WK, Wang G, Mayhew G, Li YJ, Vance JM, Martin ER. Gene-gene interaction between FGF20 and MAOB in Parkinson disease. Ann Hum Genet. 2008 Mar;72(Pt 2):157-62.

 

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 evaluating the molecular mechanisms underling these genetic associations, indentifying patient specific changes in the DNA that may contribute to the disease, 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.