Mutation patterns in axon guidance pathway can forecast susceptibility and age of onset.

A Mayo Clinic study provides evidence that explains why some people get Parkinson’s disease and predicts at what age they may develop their first symptoms. The researchers found that the joint effects of common DNA variations in several genes that encode proteins within the axon guidance pathway determine whether or not someone will suffer from Parkinson’s.

“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 researchers studied the axon guidance pathway, which includes at least 128 genes that encode proteins that play a critical role in guiding the axons of the brain during fetal development. The same proteins also repair the wiring and determine the fate of damaged brain cells later in life.

The Mayo team analyzed a dataset that included information for hundreds of thousands of common SNPs in 443 Parkinson’s patients and in 443 controls, who were unaffected siblings. Researchers identified SNPs within axon guidance pathway genes and used statistical methods to identify combinations of SNPs that were highly predictive of susceptibility to Parkinson’s, of survival free of the disease, and of the onset age for the disease. They then validated their findings using data from additional whole genome DNA and RNA variation datasets.

The models were highly effective in predicting age of onset of the disease: by age 60, 91% of patients in the highest-risk group already had Parkinson’s, while only 11% 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 findings are published in the June 15 issue of PLoS Genetics.

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