By Leigh MacMillan
November 15, 2001

The first study to search the entire human genome for regions linked to Parkinson’s disease has found evidence that multiple genes may contribute to development of the disease. The findings, reported by a multi-center team including Vanderbilt’s Program in Human Genetics, will accelerate further studies of causes and potential treatments for this devastating disease.

Parkinson’s disease is a progressive neuro-degenerative disorder affecting growing numbers of individuals - over 500,000 currently - in the United States, according to the National Institute of Neurological Disorders and Stroke. It results from the death of nerve cells in a region of the brain that controls movement, leading to tremors, shuffling gait, rigid limbs and slow movement.

Although multiple theories point to environmental or genetic causes for the disease, no one knows exactly why the movement-controlling neurons die. In fact, the relative contribution of environmental toxins versus genes to the development of Parkinson’s disease is controversial, says Jonathan L. Haines, professor of molecular physiology & biophysics and director of the Program in Human Genetics.

“Our collaborative group decided that the best way to assess whether or not there is a genetic component underlying Parkinson’s disease was to conduct a full-scale genomic screen,” he says. “At the time we started, the task of collecting enough families with multiple members affected by Parkinson’s disease was thought to be too difficult. But our group was able to bring together enough families for the study.”

The study included 174 families with two or more members diagnosed with Parkinson’s disease - 378 affected individuals out of 870 total family members. The genome-wide search linked Parkinson’s disease to distinct regions of chromosomes 5, 6, 8, 9, and 17. The findings were published November 14 in the Journal of the American Medical Association.

“This really nails down that genetics are important to Parkinson’s disease, and it’s going to refocus efforts toward looking for the genes involved,” Haines said.

Analysis of families with at least one member who developed Parkinson’s disease at an early age-less than 40 years old-showed strong evidence for linkage to the chromosome 6 region, known to include a gene called parkin. The parkin gene was previously implicated in rare inherited cases of juvenile and very early-onset Parkinson’s disease. The current results suggest that the parkin gene may be more broadly involved in the disorder.

“There’s no question that the parkin gene is associated with early-onset forms of the disease, but it looks like some people who develop Parkinson’s disease at an older age may also have defects in the parkin gene,” Haines says.

Two of the other chromosomal regions have “interesting candidate genes” nearby, Haines says.

A gene called tau, already associated with diseases that have Parkinson-like symptoms, resides near the linked chromosome 17 region. In another study published in the same issue of JAMA, the multi-center team examined the tau gene for changes called SNPs (single nucleotide polymorphisms, or “snips”). They found that a particular group of four SNPs in the tau gene was associated with increased risk of developing Parkinson’s disease.

The chromosome 9 region implicated in the genomic screen contains a gene called torsinA. Mutations in torsinA cause a movement disorder called torsion dystonia. Interestingly, Haines says, the chromosome 9 region was most strongly detected in Parkinson’s families where at least one affected individual did not respond to levodopa drug therapy, the standard treatment for Parkinson’s disease.

“This could suggest that depending on the gene variants you have, some treatments might work better or worse than others,” he says.

The investigators will more carefully examine the tau and torsinA genes for possible connections to Parkinson’s disease. For the chromosome 5 and 8 regions, they will now “zoom-in” on the identified areas to look for specific genes that may contribute to the disorder. The completed human genome sequence is expediting the search.

“For the chromosome 5 and 8 regions, we can use the genome database to examine whether these are gene-rich or gene-poor regions and what genes are there. We can get some idea of what these genes look like and prioritize our search based on potential function,” Haines says.

Identifying culprit genes will open up possibilities for improved diagnosis and presymptomatic risk assessments, Haines says. “And they open a window on the biological pathways involved in the disease, which should allow us to learn more about the disease and identify new drug targets.”

It’s not just about the genes, Haines adds. “We expect that environmental factors - things like smoking and pesticides - and genes will interact to determine an individual’s overall risk for Parkinson’s disease.

“We’re looking for the genes that elevate risk, the genes that make it more likely that you will get Parkinson’s disease, especially if you are exposed to other risk factors,” he says.

The Center for Human Genetics at Duke University coordinated the multi-center effort. Other participants included the Struthers Parkinson Center, Emory University, Ohio State University, the University of Miami, the University of Kansas, the University of Pennsylvania, the Marshfield Clinic, Baylor College of Medicine, Rush-Presbyterian-St. Luke’s Hospital, UCLA, the University of Western Australia, and GlaxoSmithKline.

The research was supported by the National Institutes of Health and GlaxoSmithKline.