|Largest-Ever Search for Autism Genes Reveals
The largest search for autism genes to date, funded in part by
the National Institutes of Health (NIH), has implicated components
of the brain’s glutamate chemical messenger system and a previously
overlooked site on chromosome 11. Based on 1,168 families with
at least two affected members, the genome scan also adds to evidence
that tiny, rare variations in genes may heighten risk for autism
spectrum disorders (ASD)*.
The study is the first to emerge from the Autism Genome Project
(AGP) Consortium, a public-private collaboration involving more
than 120 scientists and 50 institutions in l9 countries. Their
report is published online in the February 18, 2007 issue of Nature
With NIH support, the AGP is pursuing studies to identify specific
genes and gene variants that contribute to vulnerability to autism.
These include explorations of interactions of genes with other
genes and with environmental factors, and laboratory research aimed
at understanding how candidate susceptibility genes might work
in the brain to produce the disorders.
“This is the most ambitious effort yet to find the locations of
genes that may confer vulnerability to autism,” said NIH Director
Elias A. Zerhouni, M.D. “The AGP is revealing clues that will likely
influence the direction of autism research for years to come.”
“Although we know autism is highly heritable, complex gene interactions
and submicroscopic anomalies create a din of statistical noise
that drowns out detection of signals from linked sites in the genome,” explained
Dr. Bernie Devlin, University of Pittsburgh, who served as a corresponding
author on the project along with the University of Toronto’s Dr.
Stephen Scherer. “To amplify these signals, we brought to bear
gene chip technology with a huge sample, and also screened for
these fine-level anomalies, factoring them into the analysis.”
Clues emerged adding to evidence that implicates components of
the brain’s glutamate neurotransmitter system in autism. Glutamate
increases neuronal activity and plays an important role in wiring
up the brain during early development. Since autism likely stems
from faulty wiring, a genetic blueprint gone awry in this pivotal
neurotransmitter system is a prime suspect. Some key genes associated
with the glutamate system are located in chromosome regions previously
associated with autism, note the researchers.
Previous studies have also linked abnormal glutamate functioning
to disorders such as Fragile X syndrome and tuberous sclerosis,
which share some symptoms with autism. It’s not unusual for individuals
with either syndrome to be diagnosed with autism.
Among the new clues is stronger evidence for an association between
autism and sites of genes for neurexins, molecules that build glutamate
synapses — the connection machinery by which brain cells
A site on chromosome 11 most strongly linked to autism in this
study harbors genes for proteins that shuttle glutamate across
the synapse. Although detected previously, the linkage signal at
this site was regarded as less important until now.
Submicroscopic anomalies — tiny deletions, or the doubling,
tripling or even multiplying of stretches of genetic material — are
relatively common in the human genome and aren’t necessarily harmful.
However, recent evidence suggests that these anomalies may contribute
to risk for — or rarely even cause — autism if they
affect certain sites associated with the disorder. The AGP researchers
found a number of these variations in such suspect chromosomal
locations in affected individuals, including deletion of a neurexin
These anomalies can also make it more difficult to detect the
genes that more commonly account for autism risk, say the researchers.
Since each major autism candidate gene likely contributes to risk
for a relatively small percentage of families, its linkage signal
can easily be lost in the statistical noise generated by those
of the anomalies — just as a high level of static can drown
out a weak radio signal.
To amplify the power of possible linkages detected, the researchers
analyzed many subsets of data, variously excluding from the sample
factors like the submicroscopic anomalies, female sex, and ethnicity.
These analyses unmasked several suggestive linkages that would
otherwise have eluded detection.
Researchers last Fall reported (http://www.nimh.nih.gov/press/autismmetgene.cfm)
discovery of a gene version linked to autism and how it likely
works at the molecular level to increase risk. The AGP researchers
propose that multiple such gene variants, perhaps interacting with
each other and with the tiny anomalies, contribute to risk. As
more such genes are identified, studies of how they work in the
brain — in mice and other model systems — will help
to sort out the genetic and proposed environmental influences on
autism spectrum disorders, say researchers.
A second phase of AGP studies will follow up on leads suggested
in this first phase.
Gene typing and data analysis was funded by Autism Speaks (formerly
NAAR). NIH Institutes, led by NIMH, funded the recruitment and
assessment of U.S. families.
The AGP Consortium is comprised of four existing consortia: Autism
Genetics Cooperative (AGC), Autism Genetic Resource Exchange (AGRE)
Consortium, Collaborative Programs of Excellence (CPEA), International
Molecular Genetic Study of Autism Consortium (IMGSAC). Dr. Andy
Shih of Autism Speaks served as scientific manager of the project.
Principal investigators of NIH-funded components of the study
were: Joseph Buxbaum, Susan Folstein, Neil Risch, James Sutcliffe,
Daniel Geschwind, Bernie Devlin, Edwin Cook, Catherine Lord, NIMH;
Joachim Hallmayer, Margaret Pericak-Vance, James Sutcliffe, Thomas
Wassink, NINDS; Geraldine Dawson, Gerard Schellenberg, William
McMahon, Fred Volkmar, NICHD. The research was also supported by
General Clinical Research Centers at Yale University and the University
of Utah, both funded by the NCRR.
Information about Autism Spectrum Disorders:
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 NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation. For more information, visit
the Web site at http://www.nichd.nih.gov/.
The National Institute of Neurological Disorders and Stroke is
the nation’s primary supporter of research on the brain and nervous
system. More information about stroke and other neurological disorders
can be found on the NINDS web site, www.ninds.nih.gov.
The National Center for Research Resources (NCRR) provides laboratory
scientists and clinical researchers with environments and tools that
they can use to prevent, detect, and treat a wide range of diseases.
This support enables discoveries that begin at the molecular and
cellular level, move to animal-based studies, and then are translated
to patient-oriented clinical research, resulting in cures and treatments
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