Autism genes discovery suggests biological reasons for altered
8 May 2009
A research team has connected more of the intricate pieces of the
autism puzzle, with two studies that identify genes with important
contributions to the disorder.
One study pinpoints a gene region that may account for as many as 15%
of autism cases, while another study identifies missing or duplicated
stretches of DNA along two crucial gene pathways. Significantly, both
studies detected genes implicated in the development of brain circuitry
in early childhood.
"Because other autism researchers have made intriguing suggestions
that autism arises from abnormal connections among brain cells during
early development, it is very compelling to find evidence that mutations
in genes involved in brain interconnections increase a child's risk of
autism," said study leader Hakon Hakonarson, MD, PhD, director of the
Center for Applied Genomics at The Children's Hospital of Philadelphia,
and of the faculty of the University of Pennsylvania School of Medicine,
as is his main collaborator, neuroscientist Gerard D Schellenberg, PhD.
"This comprehensive research opens the door to more focused
investigations into the causes of autism disorders," said Philip R.
Johnson, MD, chief scientific officer at The Children's Hospital of
"It moves the field of autism research significantly ahead, similar
to the way oncology research progressed a few decades ago with the
discovery of specific genes that give rise to cancers. Our extensive
pediatric genomics program has pinpointed particular genes and
biological pathways, and this discovery provides a starting point for
translating biological knowledge into future autism treatments."
The hospital's Center for Applied Genomics, launched in 2006, is the
world's largest facility dedicated to the genetic analysis of childhood
Collaborating with researchers from more than a dozen institutions,
including members of the Autism Genome Project (AGP), Hakonarson led
both studies, which appear in the online version of Nature.
Autism is the best known of the autism spectrum disorders (ASDs), a
group of childhood neurodevelopmental disorders that cause impairments
in verbal communication, social interaction and behaviour.
Currently estimated to affect as many as one in 150 US children, ASDs
are known from family studies to be strongly influenced by genetics.
Previous studies have implicated several chromosome regions harboring
rare variants in raising the risk of ASDs, but until now, research has
not been consistent in identifying and replicating common genetic
One of the two studies by Hakonarson's team is the first to identify
common genetic variants associated with autism. By using highly
automated genotyping tools that scan the entire genome of thousands of
individuals, the researchers found that children with ASDs were more
likely than healthy controls to have gene variants on a particular
region of chromosome 5. That region is located between two genes,
cadherin 9 (CDH9) and cadherin 10 (CDH10), which carry codes to produce
neuronal cell-adhesion molecules.
Neuronal cell-adhesion molecules are important because they affect
how nerve cells communicate with each other, thought to be an underlying
problem in ASDs.
"These molecules are expressed on the cell surfaces of neurons, and
they are involved with shaping both the physical structure of the
developing brain and the functional connections among different brain
regions," Hakonarson said. "Although a particular gene variant may
contribute a small risk for an ASD in a particular individual, we
estimate that the variants we discovered may contribute to as many as 15
percent of ASD cases in a population — typically referred to as the
population — attributed risk of the variant."
Hakonarson's team first performed genome-wide association studies on
DNA from over 3,100 subjects from 780 families of children affected with
ASDs, then performed further studies in a cohort of 1,200 affected
subjects and 6,500 unaffected controls. They then replicated their
results in two additional independent cohorts. In total, they analyzed
DNA from 12,834 subjects.
"Autism Speaks is pleased to have facilitated this critical research,
having provided both funding and access to thousands of DNA samples
through Autism Speaks' Autism Genome Research Exchange (AGRE)," said
Geraldine Dawson, PhD, Chief Science Officer for Autism Speaks.
"Access to biomaterials and clinical data from thousands of families
through the AGRE substantially expedites the research our community
seeks and needs. Our goal is to accelerate genetic research that can
ultimately lead to improved detection and medical treatments." Dawson
also is a co-author of both studies in her role as a faculty member of
the University of Washington.
Hakonarson's second study in Nature, also using genome-wide
association tools, identified copy number variations — deletions or
duplications of DNA — that increase a child's risk of having an ASD.
Interestingly, these variants were enriched in genes that belong to two
biological pathways, one including the same neuronal cell-adhesion
molecule gene family that harbored the common variant reported in
Hakonarson's first study.
The other gene cluster impacted by copy number variations belongs to
the ubiquitin degradation pathway. Ubiquitins are a class of enzymes
that eliminate connections among nerve cells, and are involved with
processing and degrading neuronal cell-adhesion molecules — thus linking
the two gene pathways together.
"The copy number variations we discovered are active on two gene
networks that play critical roles in the development of neuronal
connectivity within the central nervous system," said Hakonarson.
"Finding genes that are biologically relevant to these neuronal systems
increases our understanding of how autism originates."
The gene discoveries, added Hakonarson, converge with evidence from
functional magnetic resonance imaging that children with ASDs may have
reduced connectivity among neural cells, and with anatomy studies that
have found abnormal development of the brain's frontal lobes in patients
"Many of the genes we identified concentrate their effects in brain
regions that develop abnormally in autistic children," said Hakonarson.
"Our current findings, when coupled with anatomical and imaging studies,
may suggest that ASDs are a problem of neuronal disconnection."
His group's ongoing research, continued Hakonarson, focuses on
investigating the exact mechanisms by which these genetic variations
cause autistic disorders. "For instance, we expect to manipulate similar
cell-adhesion genes in mice to see if the animals show altered social
behaviors that may correspond to human behaviors." In addition, other
genes remain to be discovered.
"Although we cannot immediately apply this research to clinical
treatments, these findings increase our understanding of how autism
spectrum disorders arise, and may in time foster the development of
strategies for prevention and early treatment," said developmental
pediatrician Susan E. Levy, M.D., a co-author of both studies who is the
medical director of the Regional Autism Center and a member of the
Center for Autism Research (CAR), both at Children's Hospital.
Support for both studies was provided by The Children's Hospital of
Philadelphia, the National Institutes of Health, Autism Speaks, and many
other sources, including the Margaret Q Landenberger Foundation, the
Cotswold Foundation, the Beatrice and Stanley A. Seaver Foundation, the
Department of Veterans Affairs, and the Utah Autism Foundation.
Scientists from 14 other centres in addition to Children's Hospital and
the University of Pennsylvania contributed to the discovery or
replication of the findings.
Wang et al, "Common genetic variants on 5p14.1 associate with autism
spectrum disorders," Nature, published online April 28, 2009.
Glessner et al, "Autism genome-wide copy number variation reveals
ubiquitin and neuronal genes," Nature, published online April
28, 2009. (http://dx.doi.org/10.1038/nature07953)
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