-Findings Suggest Biological Reasons for Altered Early Neural
Development-
PHILADELPHIA, April 28 /PRNewswire-USNewswire/ -- 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
percent 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, M.D., Ph.D., director of the Center for
Applied Genomics at The Children's Hospital of Philadelphia. He is on the
faculty of the University of Pennsylvania School of Medicine, as is his
main collaborator, neuroscientist Gerard D. Schellenberg, Ph.D.
"This comprehensive research opens the door to more focused
investigations into the causes of autism disorders," said Philip R.
Johnson, M.D., chief scientific officer at The Children's Hospital of
Philadelphia. "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 diseases.
Collaborating with researchers from more than a dozen institutions,
including members of the Autism Genome Project (AGP), Hakonarson led both
studies, which appear today in the online publication 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 behavior. Currently estimated
to affect as many as one in 150 U.S. 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 variants.
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, Ph.D., 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 with
autism.
"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 centers 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.
(http://dx.doi.org/10.1038/nature07999)
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)
About The Children's Hospital of Philadelphia
The Children's Hospital of Philadelphia was founded in 1855 as the
nation's first pediatric hospital. Through its long-standing commitment to
providing exceptional patient care, training new generations of pediatric
healthcare professionals and pioneering major research initiatives,
Children's Hospital has fostered many discoveries that have benefited
children worldwide. Its pediatric research program is among the largest in
the country, ranking second in National Institutes of Health funding. In
addition, its unique family-centered care and public service programs have
brought the 430-bed hospital recognition as a leading advocate for children
and adolescents. For more information, visit http://www.chop.edu.
About Autism Speaks
Autism Speaks is the nation's largest autism science and advocacy
organization, dedicated to funding research into the causes, prevention,
treatments and a cure for autism; increasing awareness of autism spectrum
disorders; and advocating for the needs of individuals with autism and
their families. Autism Speaks funds more than $30 million each year in new
autism research, in addition to supporting the Autism Treatment Network,
Autism Genetic Resource Exchange, Autism Clinical Trials Network, Autism
Tissue Program and a range of other scientific and medical programs. To
learn more about Autism Speaks, please visit http://www.AutismSpeaks.org.
SOURCE The Children's Hospital of Philadelphia
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