By expanding their search from single genes to clusters of interacting genes, researchers at the Mayo Clinic have created a model that appears to give highly accurate predictions of who will develop Parkinson’s disease and at what age. Their method may translate to the study of other complex diseases as well.
Demetrius Maraganore and his colleagues found that people who had certain patterns in their genetic sequence were 90 times more likely to develop Parkinson's disease (PD) than those who did not.
In their most recent study, reported in Public Library of Science: Genetics in June, Maraganore's team analyzed more than a half-million DNA variants found in 443 patients with Parkinson's disease and 443 unaffected relatives. The 45 high-risk PD genes researchers discovered were clustered in the biologic pathway responsible for brain development, raising speculation that environmental influences encountered during gestation might be a risk factor for the disease.
In 2004 the same researchers found their first clue that genes responsible for fetal brain development may hold some answers into the cause of Parkinson's: a single DNA variant within the axon guidance pathway, which includes at least 128 genes that encode proteins involved in wiring the brain during fetal development. These proteins also repair the wiring and influence how or if damaged brain cells will affect future health.
A 'paradigm shift'
The difference between studying gene clusters and single genes is comparable to looking at distant stars with a telescope or observing the galaxy with the naked eye. "Instead of straining to observe the effects of single DNA variants scattered randomly across the universe of the human genome, we observed the effects of a constellation of variants within a well-defined genomic pathway," Maraganore says.
The gene cluster approach offers a new way of studying complex diseases, agrees M. Maral Mouradian, professor of neurology and director of the Center for Neurodegenerative and Neuroimmunologic Diseases at the University of Medicine and Dentistry-Robert Wood Johnson Medical School in Piscataway, N.J., who was not involved in the study.
“The genomic pathway approach utilized in this study … represents a paradigm shift from the single candidate gene approach,” Mouradian says. It will be important to see if the findings can be replicated in Parkinson’s disease patients from other populations and whether clusters of genes in other pathways also play a role in this disease, she adds.
“Genomic pathway studies potentially hold considerable promise in our understanding of complex diseases such as Parkinson’s and Alzheimer’s. The proof will come from vigorous testing of candidate pathways,” says Mouradian.
Other researchers, including Arul Chinnaiyan, the director of the Michigan Center for Translational Pathology, are similarly optimistic about genetic mapping.
“Mapping of the human genome was only the beginning," Chinnaiyan says. "Equipped with the comprehensive analysis of the human genome, we can now systematically examine the blueprint of disease at the molecular level. This essential knowledge may lead to better diagnostic tests and promising new treatments for cancer, cardiovascular disease, diabetes and other illnesses.”