The overall goal of the Miami Udall center is to identify genes that cause or contribute to an individual’s susceptibility to Parkinson Disease (PD). The discovery of PD risk genes will provide insight into the biological and environmental mechanisms that cause PD. Indeed, research in many of the current Udall centers is based on a previous discovery of a single genetic mutation that directly causes PD. However, 90 to 95% of Parkinson disease is not due to single gene mutations. While the genetic contributions in this larger group of PD patients are very important, they are complex in the way they act with each other and the environment. To study the genetic contributions that affect this majority of PD patients, we have created an integrated group of researchers whose focus for the last ten years has been on using the latest genetic ideas and technology into research dissecting and identifying the genetic causes of PD. Our long-term goals include improving therapy for patients by providing important genes, genetic mechanisms and pathways that may be useful to target with drug treatment or other intervention to slow the disease. Another long-term goal is to use genetic information to identify asymptomatic individuals at high risk for PD, as early intervention is the key to preventing or significantly delaying the disease.
As mentioned, PD is a “complex” genetic disorder, not just one disease, but rather genetically and biologically heterogeneous. The interaction of many genes and environmental factors raises the risk for disease past a threshold of damage in the brain, leading to the disease. It now seems that many different starting points of disease lead to a final common PD phenotype (clinical symptoms). This is a research challenge and is one of the reasons that genetic research has been so important in our progress towards understanding the disease. Each new gene presents insight into one of these different pathways, like the flat outside or large pieces of a complex puzzle. They provide insight into how we fit the full puzzle of PD together, providing structure to researchers in many other fields working on PD. Our research seeks to continue to provide new genetic contributions to the PD puzzle.
When we started our research, the mainstream thinking was that PD had little genetic component; it was primarily an environmental disease. We know now there are multiple causal genes, many susceptibility genes and gene-environmental interactions that are important in PD. These advances have followed the growth of genetics and genomics. To apply genetics to PD requires a multidisciplinary team approach. Trained clinicians like Drs. Vance and Luca work with epidemiologists like Dr. Scott and brain banking experts like Dr. Mash to collect the best environmental data (pesticides, smoking, coffee, Vitamin D levels etc), subphenotypes (patients with dementia, sleep disorders) with the best quality biological samples for experimentation. Molecular geneticists like Drs. Vance, Dykxhoorn, Young, Wang and Nuytemans understand how to apply the technology and approaches to these samples to produce quality results, and genetic epidemiologists like Dr. Scott and statistical geneticists like Drs. Beecham and Martin have the highly refined skills to analyze the data. The era of high-throughput genotyping and sequencing also requires a large number of data management specialists and bioinformaticians.
The Miami Udall Center relies and utilizes the significant data management infrastructure of the John P. Hussman Institute for Human Genetics (HIHG), which has a long history of being leaders in management of genetic data. Our current research funding (NIH, NINDS) has three projects and contains four cores:
Project 1: Identification of Rare Variants in PD through Whole Exome Sequencing
Specific Aim I. Identify an initial set of rare variants and additional SNPs in a discovery set of 500 Parkinson Disease patients and 500 controls for testing in our replication dataset.
Specific Aim II. Identify rare variants in a large Amish pedigree.
Specific Aim III. Identify rare variants or new SNPs that are significant for contributing to the risk of developing PD in a replication dataset.
Project 2: Long ncRNAs as Epigenomic Modulators and CSF Biomarkers in Parkinson’s Disease
Specific Aim 1: Genome wide profiling of CpG methylation events in PD and control brain samples.
Specific Aim 2: Determine whether epigenetic variation plays a role as a risk factor in known Parkinson’s disease genes.
Project 3: Vitamin D Concentration, Genetic Modifiers, and Parkinson Disease
Specific Aim I. Evaluate the association of plasma vitamin D concentration with risk and age-at-onset of Parkinson Disease (PD) in three well-characterized case-control samples.
Specific Aim II. Conduct analysis to identify potential vitamin D-gene interactions underlying PD risk or age at onset.
Specific Aim III. Thoroughly examine vitamin D-associated genes for functional variants that explain their associations with PD.
- Core A: Administrative Core
- Core B: Clinical Resources Core
- Core C: Informatics Core
- Core D: Disease Modeling Core