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New Genetic 'Fishing Net' Harvests Elusive Autism Gene
Feb. 10, 2003
DURHAM, N.C. -- Duke University Medical Center researchers have developed a new
statistical genetic "fishing net" that they have cast into a sea of complex
genetic data on autistic children to harvest an elusive autism gene.
Moreover, the researchers said that the success of the approach will be broadly
applicable to studying genetic risk factors for other complex genetic diseases,
such as hypertension, diabetes and multiple sclerosis.
In this case, the gene, which encodes part of a brain neurotransmitter docking
station called the gamma-Aminobutyric Acid Receptor beta3-subunit (GABRB3), has
been implicated in autism previously, but never positively linked to the
disease. Their findings will be published in the March 2003 issue of the
American Journal of Human Genetics and is now available on the Web at http://www.journals.uchicago.edu/AJHG/journal/issues/v72n3/024607/024607.html.
"Many research groups have been actively looking for genetic risk factors that
can lead to autism, but without much success," said Margaret Pericak-Vance,
Ph.D., director of the Duke Center for Human Genetics and lead investigator of
the study.
Autism is the common term that encompasses an overlapping group of complex
developmental disorders that are diagnosed in about one in 1,000 children under
the age of 3. Each autistic child has a unique set of characteristics that
affect his or her behavior, communication skills and ability to interact with
others. It is the very diverse, complex nature of autism that has made it so
difficult to locate distinct genetic risk factors, said Pericak-Vance.
After several genetic studies turned up only a few vague genetic clues, the
research team decided a new approach was needed. Pericak-Vance hypothesized that
grouping patients with similar traits together statistically might enhance the
scientists' ability to distinguish relevant genetic risk factors. To provide
guidance, the scientists turned to Michael Cuccaro, Ph.D., a clinical child
psychologist at Duke with extensive experience diagnosing and treating autism.
Cuccaro noticed that some but not all autistic children exhibit repetitive
compulsions and extreme difficulty with changes to their daily routine. This
character trait -- defined by Cuccaro as "insistence on sameness" or "IS" --
helped the research team identify a subset of autism family data to study in
more detail.
Researchers, led by Yujun Shao, Ph.D., a genetic epidemiologist at Duke,
reorganized data collected from families in which more than one child is
affected by autism and grouped together all the families that reported their
autistic child had difficulty with change.
Cuccaro's theory that autistic children could be subdivided into at least two
groups gave the team of scientists from Duke and the University of South
Carolina an opportunity to test a new statistical method, called "ordered subset
analysis," developed by Elizabeth Hauser, Ph.D., assistant research professor of
medicine at Duke. This new genetic fishing net allows scientists to sift through
complex genetic data and extract genetic risk factors that affect only some of
the total group.
In this case, when the researchers applied the new test only to those families
whose children scored high in the IS category, they discovered a strong link to
the GABRB3 gene on chromosome 15q, where no such link had appeared before.
"This is the first successful application of ordered subset analysis to help us
pinpoint a genetic risk factor that would be missed by looking at the larger
group." said Pericak-Vance.
The researchers emphasize that this discovery is only the first step in
understanding how the GABRB3 gene, or others genes in the same region of
chromosome 15 might be involved in autism. Another clue may be gained from
previous research that has shown the same area on chromosome 15 is just as
responsible for Angelman Syndrome and Prader-Willi Syndrome -- two genetic
disorders in which a subset of affected children also exhibit repetitive
behavior. Additional research will be necessary to understand how defects in the
GABRB3 gene might contribute to autistic disorder, and how other genes or
environmental factors also play a role.
"In the short term, however, I think what this will allow us to do is encourage
clinicians and researchers working with autistic children to think about autism
as consisting of different types or subgroups and not a one-dimensional
disorder," said Cuccaro. "I think that subgrouping, over time, will allow us to
develop a better understanding of how to treat each individual with autism."
This is a case, said Cuccaro, where identifying subsets of patients based on
clinical observations has resulted in a significant neurobiological finding, and
it perhaps is pointing a way to bring clinical observations to bear on complex
genetic problems.
"The genomic revolution has given us a tremendous wealth of information in terms
of a road map and markers for finding disease genes," said Pericak-Vance. "Now,
we need to be able to look at complex clinical information and come up with
methods that can help us dissect diseases that have multiple risk factors. This
new statistical test will allow us to find meaningful genetic risk factors that
are diluted out when tested as part of a larger heterogeneous group."
Members of the research team also included Marissa Menold, Chantelle Wolpert,
Leigh Elston, Karen Decena, Shannon Donnelly, Robert DeLong, M.D., and John
Gilbert, Ph.D., of Duke; and Sarah Ravan, Ruth Abramson and Harry Wright, M.D.,
of the W.S. Hall Psychiatric Institute at the University of South Carolina. The
research was supported by grants from the National Institutes of Health and the
National Alliance of Autism Research.
Duke University Medical Center
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