The reason some people develop Parkinson’s disease while others do not, may at least in part, be hereditary. So finds a new Mayo Clinic study that provides strong evidence that the joint effects of common DNA variations in several genes influence why and at what age a person may develop the disease.
Scientists discovered the genes encode proteins within a well-defined biological pathway that largely explains why some persons get Parkinson’s disease while others don’t, and can even predict with great accuracy at what age people might develop their first symptoms.
The findings are published in the June 15 issue of PLoS Genetics.
“This represents a major paradigm shift from single gene studies to genomic pathway studies of complex diseases,” says Demetrius Maraganore, M.D., the Mayo Clinic neurologist and Parkinson’s disease specialist who led the study.
The authors say traditional genetic studies have either discovered rare single gene mutations that cause Parkinson’s disease only in isolated families, or have identified common single gene variants that are only weakly associated with the disease and inconsistently across populations.
“By examining a large cluster of related genes, we found patterns that make people up to 90 times more likely to develop Parkinson’s than the average person,” says study co-author Timothy Lesnick, a Mayo Clinic biostatistician.
“The size of the effects that we observed for genes within a pathway and the statistical significance of the predictive models were unprecedented.”
The models were highly effective in predicting age of onset of the disease: by age 60, 91 percent of patients in the highest-risk group already had Parkinson’s, while only 11 percent of patients in the lowest-risk group did.
By age 70, every member of the highest-risk group had the disease, whereas two-thirds of patients in the lowest-risk group still were disease-free. Members of the highest-risk group typically developed Parkinson’s more than 20 years earlier than the lowest-risk group.
The researchers speculate that common genetic variations within the same biological pathway might also contribute to a person’s risk of developing other brain diseases; disorders such as Alzheimer’s disease, Tourette’s syndrome, dyslexia, epilepsy and schizophrenia, need to be studied.
The study is significant because:
- 1. The genetic strategy was novel, investigating not just one, but many genes that were predicted to interact in a specific biologic pathway. This study provides a blueprint for the study of other complex diseases, which often have only modest associations with certain single genes. The summation of small effects from many genes in the same biologic pathway may be key to understanding many human diseases including Alzheimer’s, cardiovascular disease, diabetes, nicotine and alcohol dependence, and many cancers, in addition to Parkinson’s disease.
2. It provides intriguing new insights into the symptoms of Parkinson’s disease, and may lead to tests to identify persons at high risk and to new treatments to prevent the disease or halt its progression.
3. These high-risk Parkinson’s disease genes were contained in the biologic pathway for the development of the human brain, as well as repair and remodeling of brain circuits (so-called axon guidance pathway). This raises speculation for another environmental influence that heretofore has been ignored: pre-birth events in the mother’s womb.
The findings could quickly lead to genetic tests to identify persons with a high probability of developing Parkinson’s disease during their lifetime. For example, a person with high predicted probability could have a risk of Parkinson’s disease that is 90 times greater than the average person; members of intermediate-risk groups would be four to 25 times more likely to develop Parkinson’s.
The findings may also lead to development of new treatments that would promote the repair of damaged axons in the brain and spare nerve cells from early death, which could prevent or slow the progression of the disease.
Researchers say that just as subtle genetic variations within the axon guidance pathway might alter brain wiring during fetal development and predispose to Parkinson’s disease decades later in life, subtle maternal health factors also could alter brain wiring and predispose to the disease.
The researchers say effects of maternal health on the risk of Parkinson’s disease should be explored in future studies. Until now, environmental studies of Parkinson’s disease have largely focused on adulthood exposures, such as to pesticides, smoking and coffee.
These same exposures might contribute to the cause of Parkinson’s disease during gestation, they suggest.
The study was supported by grants from the National Institutes of Health, the Michael J. Fox Foundation, the National Parkinson Foundation Inc., and Gene Logic Inc.
Source: Mayo Clinic