Autism Risk Higher in People with Gene Variant
Difference in Gene Appears to Pose More Risk When Inherited from
Mothers
Scientists have found a variation in a gene that may raise the
risk of developing autism, especially when the variant is inherited
from mothers rather than fathers. The research was funded by the
National Institute of Mental Health (NIMH), part of the National
Institutes of Health.
Inheriting the gene variant does not mean that a child will inevitably
develop autism. It means that a child may be more vulnerable to
developing the disease than are children without the variation.
The gene, CNTNAP2, makes a protein that enables brain
cells to communicate with each other through chemical signals and
appears to play a role in brain cell development. Previous studies
have implicated the gene in autism, and in this study researchers
were able to link a specific variation in its structure to the
disease.
Results of the study were reported online January 10 in the American
Journal of Human Genetics, by Aravinda Chakravarti, Ph.D.,
Dan E. Arking, Ph.D., and colleagues from the Johns Hopkins University
School of Medicine, with Edwin Cook, M.D., and colleagues from
the University of Illinois at Chicago.
"Autism is highly heritable. Identifying the genes involved
is crucial to our ability to map out the pathology of this isolating
and sometimes terribly disabling disease, which currently has no
cure," said NIMH Director Thomas R. Insel, M.D.
Autism is a developmental brain disorder that impairs basic behaviors
needed for social interactions, such as eye contact and speech,
and includes other symptoms, such as repetitive, obsessive behaviors.
The symptoms sometimes cause profound disability, and they persist
throughout life. Treatments may relieve some symptoms, but no treatment
is fully effective in treating the core social deficits.
Although the cause of autism is not yet clear, studies of twins
have shown that genes play a major role. It is likely that variations
in many genes, influenced by environmental factors, interact during
brain development to cause vulnerability to the disease. These
genes have yet to be identified. Several candidates, including CNTNAP2,
have been suggested.
The assertion that the CNTNAP2 gene appears to be involved
is strengthened by the fact that each of the different analytical
approaches the researchers used in this study led to the same conclusion.
Results were replicated in a second, larger group of participants,
further implicating the gene. Together, the two groups of participants
comprised one of the largest autism studies reported to date.
The first part of the study included 145 children with autism
and their parents, families that had two or more children with
autism. Using a technique called genome-wide linkage analysis,
the researchers found that a chromosome, 7q35, appeared to be linked
to the disease.
Looking deeper into that chromosome, they identified a gene — CNTNAP2 — that
contained a variant relevant to autism. Where a single segment
of the genetic code could contain either the chemical base adenine
or thymine, children with autism tended to have inherited the thymine
variant.
To validate these findings, the researchers studied a separate
group of participants; 1,295 children with autism and their healthy
parents. The scientists again found that children with autism had
higher rates of the thymine variant in the CNTNAP2 gene
than would be expected to occur by chance.
When the researchers combined the data from the studies, they
found that children with autism were about 20percent more likely
to have inherited the thymine variant from their mothers than from
their fathers.
"This is a common variant. People inherit it all the time.
Our finding that it's associated with autism more often when it's
inherited from mothers is intriguing, but needs to replicated," Chakravarti
said.
The role of CNTNAP2 in brain-cell development suggested
by earlier studies has to do with differentiation, the process
by which precursor cells develop into the different kinds of cells
of the body. CNTNAP2 carries the genetic code for a protein,
part of a family called neurexins, that appears to enable the precursor
cells to develop myelinated axons. These are projections through
which brain cells send each other electrical impulses essential
for normal brain function at especially high speeds.
"CNTNAP2 is an excellent candidate gene for autism," Chakravarti
said. "It encodes a protein that's known to mediate interactions
between brain cells and that appears to enable a crucial aspect
of brain-cell development. A gene variant that altered either of
these activities could have significant impact."
For more information about autism, visit the NIMH website at http://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-pervasive-developmental-disorders/index.shtml.
More information about autism also is available from the Department
of Health and Human Services (DHHS) website at http://www.hhs.gov/autism/.
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
the NIMH website: http://www.nimh.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Reference:
Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea
A, Guy M, Lin S, Cook Jr. EH, Chakravarti A. A common Genetic Variant
in the Neurexin-Superfamily Member CNTNAP2 Increases Familial Risk
of Autism. American Journal of Human Genetics, online ahead
of print, January 10, 2008.
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