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Brain Wiring Genes Tied to Parkinson's and ALS

By Michael Smith, North American Correspondent, MedPage Today
Published: January 16, 2008

Demetrius Maraganore, M.D., Mayo Clinic

MINNEAPOLIS, Jan. 16 -- Susceptibility to both amyotrophic lateral sclerosis and Parkinson's disease, along with age of onset and survival, may be controlled by a constellation of genes involved in brain wiring, researchers here said.

The variations are in two overlapping groups of genes in the so-called axon guidance pathway, Demetrius Maraganore, M.D., of the Mayo Clinic, and colleagues, reported online in PLoS ONE.

The genetic links "may provide important insights into the causes of these and related neurodegenerative disorders," Dr. Maraganore and colleagues said

Note that this study suggests that variations in an overlapping group of genes involved in brain wiring may play a central role in the diseases.
The axon guidance pathway, he said, plays a key role in guiding axonal development in the fetal brain and also repairs axons and determines the fate of damaged brain cells later in life.

It's intuitively clear, he said, that the pathway "must be important to brain health."

For the ALS part of this study, the researchers examined 4,133 single nucleotide polymorphisms (SNPs) in 124 genes of the pathway that are expressed in the brain. For Parkinson's, they examined 3,095 SNPs within 122 of those genes.

Using a publicly available genomic data set that included 270 ALS patients, 270 patients with Parkinson's, and 270 healthy controls, they employed logistic regression tools to find associations between the SNPs and the diseases.

For both diseases, about 10% of the SNPs were associated with susceptibility, survival, and age at onset for each disease but the exact set of SNPs varied slightly depending on which of the three outcomes was studied.

In a stepwise fashion, the researchers then added SNPs together and tested their predictive value in combination. The final model for each outcome was divided into quartiles of risk.

Finally, they constructed odds ratios, with the lowest risk category serving as a reference group, Dr. Maraganore and colleagues said.

In the case of susceptibility to ALS, for instance, those in the highest risk category were nearly 2,000 times as likely to get the disease as those in the lowest group. The odds ratio was 1,739.73, with a 95% confidence interval from 523.53 to 5,781.32.

The researchers calculated the significance of the pathway (as opposed to the individual SNPs) at P=2.92x10-60.

For the corresponding risk groups in Parkinson's disease, the odds ratio for susceptibility was 391.82, with a 95% confidence interval from 157.94 to 972.06. The significance of the pathway was calculated to be P=8.10x10-71.

The final model predicting ALS susceptibility contained 31 genes, and the final model predicting PD susceptibility contained 39. Twenty-four of the genes were shared.

The susceptibility model for ALS had 94% sensitivity and 94% specificity, while the Parkinson's model had 92% sensitivity and 92% specificity, Dr. Maraganore and colleagues said.

Results were similar for the other two outcomes in the two diseases, the researchers said, although the numbers and exact genes involved varied slightly.

Dr. Maraganore said the methods involved may have even wider application.

The finding is "powerful proof of principle that we are on the verge of seeing genomic tests that will predict a whole host of complex diseases," he said.

Yet Dr. Maraganore cautioned that the model should not be thought of as the groundwork for a genetic test, adding that more research will be needed before that is possible.

But in the long run, he said, it may be possible to use similar information to "begin development in a more focused manner of treatments for both ALS and Parkinson's disease."

The research was supported by the NIH and the Michael J. Fox Foundation. Dr. Maraganore reported a provisional application for a patent on some of the technology used in this study.

http://www.medpagetoday.com/Neurolog...rology/tb/7982
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