October 24, 2003

Team pinpoints gene influencing age-at-onset of Alzheimer’s, Parkinson’s

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Nancy Wells

Team pinpoints gene influencing age-at-onset of Alzheimer’s, Parkinson’s

A multi-center team, including Vanderbilt’s Program in Human Genetics, has identified a gene that appears to affect the age at which an individual begins to show symptoms of Alzheimer’s or Parkinson’s disease. The gene does not alter an individual’s risk of having the diseases, the investigators reported Oct. 21 online in Human Molecular Genetics.

Identifying genes that control “age-at-onset” could lead to therapies that delay disease onset beyond the natural lifespan.

“If you could develop a drug that would slow down the neurodegenerative process by five years, you would prevent a significant portion of Alzheimer’s disease,” said Jonathan L. Haines, Ph.D., the T. H. Morgan Professor of Human Genetics and director of the Program in Human Genetics.

Alzheimer’s and Parkinson’s disease are progressive neurodegenerative disorders that together affect over five million people in the United States, according to the National Institutes of Health.

The investigators used a new approach they call “genomic convergence” to focus more quickly on potential age-at-onset genes. The approach relies on multiple lines of genomic evidence to find genes that are involved in the disease process.

In the current research, the investigators used two sources of data — their previous study that linked a region of chromosome 10 with age-at-onset in Alzheimer’s and Parkinson’s disease and new microarray experiments comparing the expression of genes in brain tissue from Alzheimer’s patients and control patients.

Both linkage analysis and microarray studies can yield hundreds of gene “candidates,” and sorting through them can take years, Haines said. Finding the genes that are present in both sets of data — converging the genomic data — speeds this process.

“It’s a way of narrowing down the search and putting together as much existing information as possible to pick the best candidate genes,” Haines said.

In the current study, the genomic convergence approach turned up four genes that were over- or under-expressed in Alzheimer’s brain tissue and that were also present in the chromosome 10 linkage region. The investigators then looked for evidence that any of these four genes were associated with age-at-onset of Alzheimer’s or Parkinson’s by tracking variants of each gene. They found that a particular variant of one gene, GSTO1 (glutathione S-transferase, omega 1), was associated with a later than average onset of disease.

The finding is intriguing, the investigators wrote, because recent studies have suggested that GSTO1 is involved in processing the inflammatory protein interleukin-1beta. Inflammation is thought to play an important role in neurodegenerative diseases like Alzheimer’s and Parkinson’s.

GSTO1 does not alter an individual’s risk of getting the diseases, “but in a susceptible person, it may influence the rate of degeneration — having a faster or slower neurodegenerative process,” Haines said. Other genes in the inflammatory pathway might confer elevated or reduced risk for these diseases, he added.

Identifying age-at-onset genes adds to ongoing efforts to define genes that influence risk for neurodegenerative diseases. “Ideally we will be able to find ways to delay disease onset and lower risk,” Haines said.

The association of GSTO1 with both Alzheimer’s and Parkinson’s disease supports the premise that these disorders share underlying biological mechanisms.

“An inflammatory pathway and the neuronal cell death it causes might be common to multiple neurodegenerative diseases, including Alzheimer’s and Parkinson’s,” Haines said.

The Center for Human Genetics at Duke University, led by Margaret A. Pericek-Vance, Ph.D., coordinated the multi-center effort. The research was supported by the National Institutes of Health, the American Federation for Aging Research, the Alzheimer’s Association, the Institut de France, and GlaxoSmithKline Inc.